L. Lee Hamm Nazih L. Nakhoul
Carbonic Anhydrase and CO2 Transport, 248
Carbonic Anhydrase, 248
CO2 Transport, 250
Proximal Tubule, 250
Mechanisms of H+ and HCO3- Transport, 251
Regulation of Proximal Tubule Acid-Base Transport, 254
Loop of Henle and Thick Ascending Limb, 257
Regulation of HCO3- Transport in the Thick Ascending Limb, 258
Distal Nephron, 259
Distinct Features of Specific Distal Tubule Segments, 260
Cellular Mechanisms of H+ Secretion and HCO3- Reabsorption, 262
Cellular Mechanisms of HCO3- Secretion, 264
Regulation of Distal Nephron Acid-Base Transport, 265
Ammonium Excretion, 266
NH4+ and NH3 Transport, 267
The kidneys have two major roles in acid-base homeostasis: (1) reabsorption of the bicarbonate (HCO3-) filtered at the glomerulus (≈4000 mmoles to 4500 mmoles per day depending on glomerular filtration rate (GFR) and plasma bicarbonate); and (2) excretion of acid and ammonium (NH4+) to accomplish production of “new” bicarbonate to replace that consumed by dietary or endogenous metabolic acids. As will be discussed, both functions rely on H+secretion in the various segments of the nephron. Dietary and endogenous acids usually amount to about 1 mEq/Kg body weight per day on a typical Western diet. Regarding the reabsorption of filtered HCO3-, the proximal tubule accounts for the majority (≈75% to 80%) of this reabsorption as illustrated in Figure 7-1 . Without this reabsorption, as in proximal renal tubular acidosis, HCO3- spills into the urine, lowering plasma HCO3- and causing metabolic acidosis. However, normally almost all of the filtered HCO3- is reabsorbed.
The second function of the kidneys is to generate “new” HCO3-; “new” HCO3- refers to HCO3- that is produced by the kidneys, but that was not filtered at the glomerulus. Production of new HCO3- is also critical in regulating plasma HCO3- concentration and hence acid-base balance. This is accomplished in two ways: excretion of titratable acid (TA) and excretion of NH4+. Titratable acid refers to acid excreted that has titrated urinary buffers. Titratable acid equals the amount of acid (H+) that is added to tubular fluid along the nephron, thus titrating urinary buffers. Titratable acid is a function of both urine pH and buffering capacity. Excretion of H+ (or the equivalent) produces HCO3- in a HCO3-/CO2 buffered physiologic system in which pCO2 is in essence fixed by pulmonary excretion. Although HCO3-/CO2 is not the only physiologic buffer system, it reflects the status of all the physiologic buffers. Phosphate is the principal urinary buffer, but creatinine, citrate, and a variety of organic solutes also function as urinary buffers to some extent.
Urinary NH4+ accomplishes production of “new” HCO3- and excretion of acid indirectly; in contrast to prior concepts this does not occur directly via NH3 acting as a proton acceptor (NH3 + H+ ↔ NH4+). Total ammonia, NH3 + NH4+, is predominantly NH4+ at physiologic pH (because the pKa of NH4+ is ≈9) as discussed subsequently. Excretion of NH4+ produces “new” bicarbonate from the metabolism of glutamine to HCO3- and NH4+. Addition of HCO3- to plasma is the physiologic equivalent of acid excretion.
The production of new HCO3-, or equivalently excretion of acid, is quantified as net acid excretion (NAE). Urinary NAE is usually calculated as
NAE = NH4+ + TA - HCO3-.
Urinary HCO3- is subtracted because the loss of a HCO3- in the urine is equivalent to the gain of acid. Urinary HCO3- is usually small. The urine also contains a variety of organic anions such as citrate, which if retained, rather than excreted, could be metabolized to HCO3-. However, this loss of organic anions has not traditionally been thought to contribute to overall acid-base balance in humans (see discussion of organic acids).
This chapter will cover carbonic anhydrase, then the mechanisms of acid-base transport along the nephron and separately the generation and excretion of NH4+. Carbonic anhydrase is important in most nephron segments for acid-base transport and will be covered initially. The prior editions of this text have thoroughly reviewed the development of current concepts of acid-base transport and therefore some aspects that were covered extensively before will be abbreviated. References are selective with emphasis on more recent work. More extensive historical references have been provided in earlier editions.
Prior decades of study of acid-base physiology focused on identifying mechanisms of acid-base transport along the nephron. After clearance studies that relied on indirect inferences about specific nephron segment transport properties, initial studies of proximal tubule transport beginning in the 1960s used in vivo micropuncture of rat superficial proximal tubules. Begin-ning in the late 1970s, in vitro microperfusion studies, using rabbit and later rat and mouse, expanded the types of studies that could be performed  ; in vivo microperfusion of rat proximal tubules later accomplished similar control of both luminal and basolateral composition. In a similar time frame, studies of transport by membrane vesicles, particularly from the apical and basolateral membranes of the proximal tubule, were extremely valuable in identifying and characterizing mechanisms of acid-base transport. The past decade has been noted for the molecular identification and understanding of acid-base transporters, and the signaling that regulates them; emphasis will be placed on these aspects.
FIGURE 7-1 Model of over-all bicarbonate reabsorption and lumen pH profile along the nephron. Derived from data in control rats in references 162 and 163. pH and HCO3- concentration values are shown for the following sequential nephron segments: early superficial proximal tubule (EPT), late superficial proximal tubule (LPT), bend of Henle's loop (loop), early superficial distal tubule (EDT), and late superficial distal tubule(LDT). FD is fractional delivery of HCO3- to those sites where measured. The pCO2 in the renal cortex has been determined to be ≈65 mm Hg.     See text for additional details.
CARBONIC ANHYDRASE AND CO2 TRANSPORT
Carbonic anhydrase (CA) is an important aspect of HCO3- transport all along the nephron. This zinc metalloenzyme catalyzes the reversible reaction    :
CO2 + OH- ↔ HCO3-
In physiologic solutions this is equivalent to the more commonly written equation:
CO2 + H2O ↔ H2CO3 ↔ HCO3- + H+
The uncatalyzed rate of this reaction is very slow, but the catalyzed rate with carbonic anhydrase is accelerated by several orders of magnitude. The presence of CA both inside cells and on the apical and basolateral membrane of tubular epithelial cells greatly accelerates acid-base transport, particularly HCO3- reabsorption. In the absence of CA, H+ secretion into the tubule lumen will result in an H+ concentration significantly above equilibrium values (a lower pH-H+ higher-than equilibrium due to the slow equilibration of the previous equation going from right to left). This is a so-called acid disequilibrium pH. A higher H+ concentration (lower pH) will impede further H+secretion whether via Na-H exchange or H+ ATPase, the two main mechanisms of H+ secretion (discussed later). The mammalian isoenzymes appear to share three zinc binding histidine residues; the bound zinc metal is crucial for the functional activity of CA.  
Because of the importance of CA for acid-base transport, the distribution of CA in the kidney has been studied for many years. Initially these studies used histochemical approaches (Hanson's cobalt-phosphate) to detect hydratase activity in tissue sections. Later studies used functional approaches with CA inhibitors. More recent studies have used immuncytochemical methods and molecular methods to detect mRNA for specific isoforms of CA. A great difficulty in integrating these studies is the apparent differences among experimental species and humans. An additional difficulty has been differences between varying techniques and even different antibodies in the same species. These differences have been well reviewed earlier.   
Although there are more than a dozen isoforms of mammalian CA, two isoforms of carbonic anhydrase have been best studied in the kidney, cytosolic CA II and membrane bound CA IV. CA II is present in most cells along the nephron involved in acid-base transport. CA II is quite sensitive to inhibition by a variety of sulfonamides. In the proximal tubule, cytosolic CA functions to continuously provide both cellular H+ for luminal secretion and HCO3-for extrusion across the basolateral membrane (see model figures in later sections); both H+ and HCO3- derive from H2O and CO2 as in the earlier equation. Similar functions pertain to both H+ secretion and HCO3- secretion in more distal nephron segments. An important, but still not completely defined, aspect of CA function now appears to be direct binding and interaction with HCO3- transporters such as AE1 and NBC1  ; such interactions may also extend both to other CA, such as CA IV, and to other acid-base transporters such as NHE1.    CA II also appears to be important in the development of intercalated cells of the collecting duct.
CA IV is less abundant but critically important in several nephron segments, particularly the proximal tubule where large amounts of HCO3- are reabsorbed.   The apical distribution of CA IV is shown in Figure 7-2 . CA IV is bound to the apical membrane by a glycosylphosphatidylinositol (GPI) moiety. The presence of functional luminal CA prevents a spontaneous acid disequilibrium pH that would inhibit significant HCO3- reabsorption (see later discussion of proximal tubule). Usually a GPI linkage is only associated with apical localization of a membrane protein, but CA IV is also found in the basolateral membranes of some nephron segments (not shown well in Figure 7-2 , but well documented). The mechanism of basolateral localization (such as alternately spliced isoform of CA IV or immunologically overlapping isoform) is unknown. CA IV is present on the basolateral membrane of the proximal tubule, probably facilitating HCO3- efflux from the cell.    CA IV is also present on the apical and basolateral membranes of the thick ascending limb (TAL).
FIGURE 7-2 CA IV staining distribution. A, Corticomedullary boundary of a rat kidney. On left, apical aspects of S2 segments of the proximal tubule within the cortex are heavily stained for CA IV. On right, proximal S3 segments in the outer stripe of the outer medulla are negative. With other methods basolateral membranes were also stained. Thick ascending limbs (arrows) are positive, but collecting ducts (CD) are unstained. B, Outer stripe of the outer medulla. The CA IV-positive tubules are thick ascending limbs of Henle (arrows). The proximal S3 segments are unstained, and both intercalated and principal cells in collecting ducts (CD) are negative. (From Brown D, Zhu XL, Sly WS: Localization of membrane-associated carbonic anhydrase type IV in kidney epithelial cells. Proc Natl Acad Sci U S A 87:7457–7461, 1990.)
The importance of membrane bound CA, as distinct from cytosolic CA, has been studied using relatively impermeant CA inhibitors such as benzolamide and also CA inhibitors chemically bound to polymers such as dextran. Such inhibitors can block activity of extracellular CA, but presumably not cytosolic CA. These studies have demonstrated a critical role of both luminal and basolateral membrane bound CA in the proximal tubule.    Similar studies have also demonstrated the importance of luminal carbonic anhydrous in some distal nephron segments such as the inner stripe portion of outer medullary collecting duct. Direct studies of luminal pH have also been used to establish the presence or absence of functional luminal CA. These studies suggest that most segments of the collecting duct and the final portion of the proximal tubule, the S3 segment, do not have luminal CA.     However, some segments of the distal tubule and collecting duct (inner stripe portion of the outer medullary collecting duct in rabbit and initial inner medullary collecting duct of rat) have functional luminal CA.   Those nephron segments without luminal CA are expected to secrete H+ or reabsorb HCO3- at lower rates and luminal pH will be lower (for the same rate of H+ secretion). The lower luminal pH particularly in the distal collecting duct may augment NH4+ secretion by keeping NH3 concentration lower (see later discussion).
Recent studies demonstrate that both CA II and CA IV increase with metabolic acidosis, facilitating increased rates of acid-base transport.   
Two other isozymes of membrane bound CA have been recently found in kidney, CA XII and CA XIV.    CA XII is in the basolateral membranes of the TAL, the distal tubule, and principal cells of the collecting duct.   CA XII is also present in the proximal tubule and collecting tubules of some species. CA XIV is present in the proximal tubule and thin descending limb. Identifying the functional roles of these enzymes and integration of these findings with prior studies of CA activity will be important in the future.
Despite the importance of CA, complete inhibition of CA activity in vivo only reduces whole kidney HCO3- reabsorption by 30% to 40%. In vivo, the proximal tubule continues to reabsorb 20% of the filtered load, and the loop of Henle and distal nephron reabsorb significant HCO3-.   The mechanism of the residual HCO3- reabsorption in vivo appears to be HCO3- gradients from tubule lumen to interstitium during luminal volume absorption.  Consistent with this mechanism, little if any HCO3- reabsorption occurs in nephron segments perfused in vitro during CA inhibition; in this case there are only small transepithelial HCO3- gradients.
CO2 diffusion across cell membranes is critical for HCO3- transport, as discussed in the section on the proximal tubule in particular. For instance, CO2, with H2O, provides for the cellular H+ to be secreted across the apical membrane and HCO3- to be transported across the basolateral membrane. Rapid CO2 diffusion across cell membranes is predictable based on high lipid solubility of CO2. And in fact, very high CO2 permeability has been measured in intact proximal tubules.   However, CO2 diffusion through aqueous solutions is facilitated by CA.  
Surprisingly, measurements of pCO2 in most structures of the renal cortex reveal levels higher than arterial pCO2 (or renal venous blood) by as much as 25 mm Hg.     This has been attributed to the process of H+/HCO3- transport in the proximal tubule, but more importantly to metabolic CO2 production, coupled with a counter-current type vascular exchange of CO2 in the cortex.    
The urine pCO2 is also significantly greater than arterial pCO2 during bicarbonaturia; in fact, the urine minus blood pCO2 gradient has been used to index distal nephron H+ secretion. The origin of the elevated urine pCO2 derives from H+ secretion into the collecting duct lumen, combining with HCO3-.   In this setting two factors contribute to the high CO2: first, slow uncatalyzed rate of CO2 formation in the absence of luminal CA in the collecting duct lumen, and second, the countercurrent system in the medulla and low surface area:volume ratio in the renal pelvis and remaining urinary tract, slowing diffusion of CO2.   
The proximal tubule reabsorbs 75% to 80% of the filtered bicarbonate. The general features of HCO3- reabsorption are shown in Figure 7-3 : apical H+ secretion, basolateral Na+ coupled HCO3- exit from the cell, and facilitation by both membrane bound and cellular carbonic anhydrase. Apical H+ secretion occurs by both an apical Na-H exchanger and a H+-ATPase. The apically secreted H+ reacts with luminal HCO3- to form CO2 and H2O that are readily permeable across all membranes of the proximal tubule. This initial process removes luminal HCO3-. To complete the process of net transepithelial HCO3- reabsorption, cellular HCO3- derived from CO2 + H2O is transported across the basolateral membrane. Both the apically secreted H+ and the basolaterally transported HCO3- derive from CO2 + H2O ➙ HCO3- + H+; the CO2 can be conceptualized as derived from luminal HCO3-➙ CO2. Each of the reactions of HCO3- + H+ ↔ CO2 + H2O (in the lumen net HCO3- + H+ ➙ CO2 + H2O; in the cell, net CO2 + H2O ➙ HCO3- + H+) is catalyzed (accelerated) by carbonic anhydrase, both cytoplasmic and membrane bound on the apical and basolateral membranes; in the absence or inhibition of carbonic anhydrase, net transepithelial HCO3- reabsorption is markedly inhibited.
FIGURE 7-3 Model of HCO3- reabsorption in the proximal tubule. See text for details.
The proximal tubule is composed of three specific subsegments (S1, S2, and S3) and differs between juxtamedullary and superficial nephrons   ; the acid-base transport in these subsegments differ both quantitatively (e.g., S1 higher rates of transport than S3) and qualitatively to some extent as will be discussed in more detail later.   However, many of the mechanisms and regulation of acid-base transport are similar among these areas. The main differences appear to be lower rates of HCO3- reabsorption and some different mechanisms in the late proximal tubule (identified as the terminal proximal straight tubule).
Mechanisms of H+ and HCO3- Transport
Conceptually, HCO3- reabsorption could occur by either direct HCO3- (or base) reabsorption, or secretion of acid (or H+). The mechanism of HCO3- reabsorption was determined to be H+ secretion rather than direct HCO3-reabsorption more than three decades ago. Investigators demonstrated an acid disequilibrium pH using microelectrodes in the proximal tubule lumen during carbonic anhydrase inhibition.   An acid disequilibrium pH (explained earlier) implies H+ secretion, rather than base absorption. The acid disequilibrium pH was only seen with inhibition of luminal CA because normally membrane bound CA is active in the proximal tubule.
HCO3- reabsorption across the luminal membrane was also found to be sodium dependent, chloride independent, and electroneutral.    Subsequently, studies demonstrated that the mechanism of H+ secretion involves a Na-H exchanger that exchanges one luminal Na+ for one cellular H+; this was shown first using brush border membrane vesicles and later with intact tubules.    Membrane vesicle experiments demonstrated acid transport with an imposed sodium gradient, and sodium transport with an imposed pH gradient. Additional vesicle experiments demonstrated that the Km for Na+ is ≈5 μM to 15 μM and that the exchanger is sensitive to amiloride and its analogs.   Similar features were subsequently found in intact tubules.     The high affinity (low Km) for sodium implies that the exchanger will always be maximally saturated for sodium in the proximal tubule in vivo. The competitive inhibition by amiloride and its analogs has been a key feature in identifying Na-H exchangers experimentally.   This exchange process is responsible for ≈⅔ of proximal HCO3- reabsorption and is also the major mode of Na+ reabsorption in the proximal tubule. The driving force for transport is the Na+ concentration gradient from lumen to cell (≈140 μM and ≈10–20 μM in lumen and cell, respectively) maintained by basolateral Na-K ATPase. The luminal Na+ concentration is constant ≈140 mEq/L along the length of the proximal tubule due to the near equivalent reabsorption of Na+ and water.
The apical membrane Na-H exchanger has now been determined to be NHE-3 (Na-H Exchanger 3), a member of the ubiquitous family of Na-H exchangers that regulate intracellular pH and volume, and respond to growth factors, in many cell types. NHE-3 is a 93 kD molecule with 10-13 transmembrane domains and consensus phosphorylation sites for PKA and PKC.    NHE-3 is distinct from NHE-1, the first cloned and more ubiquitous Na-H exchanger, particularly in tissue distribution and regulation. In contrast to the presence of NHE-1 in most cell types and on the basolateral aspect of many epithelial cells, NHE-3 is restricted to the kidney (predominantly cortex) and intestine, and in these cell types is located on the apical membrane. The regulatory mechanisms are also quite distinct. Many of the molecular features of NHE-3 have been determined and are discussed elsewhere in this volume and also recently reviewed.   Immunohistochemical studies and studies of NHE-3 knockout animals are the most definitive in indicating a predominant role for NHE-3 in mediating most of proximal HCO3- reabsorption.          In NHE-3 knockout mice, proximal tubule HCO3- and volume reabsorption is significantly reduced (leaving most remaining HCO3- reabsorption mediated by a bafilomycin sensitive mechanism); a mild acidosis is present, partially compensated by increased distal tubule acid secretion.    This is illustrated in Figure 7-4 , which shows the overall reduction of HCO3- and fluid reabsorption in NHE-3 knock-out animals, the lack of response to the amiloride analog EIPA, and the bafilomycin sensitive HCO3- reabsorption (related to H+-ATPase discussed later) in both control and knock-out animals. Immunohistochemical studies have demonstrated NHE-3 appropriately localized to the apical membranes of proximal tubules (and thick ascending limbs) ( Fig. 7-5 ).   Some evidence has supported the possible role of other (possibly unidentified) NHE isoforms in proximal tubule apical transport,   but this remains controversial. Some studies have suggested a possible role for NHE-2, but most immunohistochemical studies and knock-out mice do not suggest a proximal tubule location or function.    Similarly, NHE-1 deficient animals do not have systemic acid-base abnormalities. However, Na-H exchange in the late proximal tubule may not be NHE-3. Recently NHE-8 has been localized to the proximal tubule and may play a role in acid excretion. The exchanger in the proximal tubule also transports other cations such as lithium and NH4+93,94 (see later discussion). An important physiologic feature is that the transport rate of the apical Na-H exchanger is augmented by intracellular acidosis via both kinetic and allosteric mechanisms (see later discussion).
FIGURE 7-4 HCO3- and fluid reabsorptive rates (JHCO3 and Jv, respectively) in wild-type and NHE3 null mice. Effects of inhibitors: EIPA, ethylisopropylamiloride to inhibit Na-H exchange; BAF, bafilomycin to inhibit H+-ATPase; SCH, Sch-28080 to inhibit H-K-ATPase. *Significant difference from control (P < 0.05). (From Wang T, Yang CL, Abbiati T, et al: Mechanism of proximal tubule bicarbonate absorption in NHE3 null mice. Am J Physiol 277:F298–F302, 1999.)
FIGURE 7-5 Immunohistochemical demonstration of NHE-3 distribution in the rat kidney. Shown are staining in the apical membranes of proximal tubules (P) and thick ascending limb (T), but no staining in the distal tubule (D) or glomerulus (G). A, Cortical labyrinth, Immunostaining fro NHE-3. The proximal brush border is stained from the beginning of the proximal tubule (P). The luminal membranes of the macula densa cells (MD) are weaker stained than those of thick ascending limb cells. NHE-3 protein staining ceases at the transition (arrow heads) of the thick ascending limb (T) to the dista convoluted tubule (D). B, Medullary ray. Immunostaining for NHE-3 showing that the luminal membranes of thick ascending limbs (T) are heavily stained, collecting ducts (CD) are unstained; weak staining of S2 segments of the proximal tubules in the medullary ray compared to strong staining of S1 in the cortex. (From Amemiya M, Loffing J, Lotscher M, et al: Expression of NHE-3 in the apical membrane of rat renal proximal tubule and thick ascending limb. Kidney Int 48:1206–1215, 1995.)
The proximal tubule also has a second mechanism of H+ secretion, a Na+ independent electrogenic ATPase that was first identified in membrane vesicles. Subsequent work has identified this as an apical membrane, multi-subunit vacuolar type H+ATPase like that in the distal nephron, discussed later.      In addition to the vesicle studies, experiments in intact tubules have also been consistent with an apical H+ATPase: electrophysiologic studies showing a lumen positive voltage in the appropriate setting, cell pH measurements demonstrating Na+ independent intracellular pH recovery from acid loads, and response of HCO3- reabsorption and cell pH to inhibitors of H+ATPase.     The vacuolar H+ATPases are blocked by DCCD (N,N′-dicyclohexylcarbodiimide), NEM (N-ethylmaleimide), and more specifically by bafilomycin A1.   The most convincing evidence has been the immunocytochemical staining for subunits of the vacuolar H+-ATPase. The H+ATPase mechanism accounts for much, if not all, of the remaining ⅓ of HCO3- reabsorption in the proximal tubule not mediated by Na-H exchange. This is illustrated by the knock-out of NHE-3 experiments in Figure 7-4 .
The proximal tubule apical membrane also exhibits Cl-/base (OH- or HCO3-) exchange,      but the role in acid-base transport is doubtful because net HCO3- reabsorption is independent of Cl-.   The predominant role of Cl-/base exchange is in fluid reabsorption. Cl-/base exchange in parallel with Na-H exchange (Na and Cl- moving into the cell, and H+ and base moving into the lumen) will result in no net effect on acid-base transport but result in NaCl absorption. The apical membrane also has other Cl-/anion exchangers (the anions formate and oxalate in particular) that can augment net NaCl reabsorption, but these are probably not involved in HCO3-reabsorption  ; the transporter SLC26A6 (CFEX, PAT1) is probably at least one of the responsible transport proteins.   
Basolateral HCO3- extrusion from the proximal tubule cell is also necessary to accomplish net transepithelial HCO3- reabsorption (see Fig. 7-3 ). HCO3-, derived from CO2 and H2O in the presence of cytoplasmic CA, is transported into the basolateral interstitium and capillary blood. The major mechanism of this was first suggested from experiments on salamander proximal tubules; these experiments demon-strate that changes in basolateral HCO3-or sodium concentration simultaneously altered intracellular pH and sodium concentration, and altered basolateral membrane voltage ( Fig. 7-6 ). These changes were independent of Cl- and sensitive to 4-acetamido-4-isothiocyanostilbene-2,2′-disulfonate (SITS). Subsequent experiments using mammalian tubules     and basolateral membrane vesicles   demonstrated results consistent with coupled Na and HCO3- co-transport, carrying negative charge (more HCO3- than Na transported). The driving force for basolateral Na-HCO3- co-transport is the cell negative transmembrane voltage, maintained by the high cell-to-interstitium K+ gradient. To achieve basolateral HCO3- extrusion based on the known ionic content and voltage of the proximal tubule, the stoichiometry should be three HCO3- per Na+127,128; this has been demonstrated both in tubules and in membrane vesicles.   Several studies demonstrated that the transported base is HCO3- and not OH-.    Carbonate (CO3-2) has been suggested by one study to be a transported species; it would be the electrical and acid-base transport equivalent of two HCO3-. This has not been confirmed with the cloned transporter, discussed later.
FIGURE 7-6 Electrogenic Na-HCO3- co-transport in the basolateral membrane of the Ambystoma proximal tubule. VI and V3 represent basolateral membrane potential and transepithelial potential, respectively. Basolateral Na+ removal causes both cell acidification and basolateral depolarization. Basolateral SITS (4-acetamido-4-isothiocyanostilbene-2,2′-disulfonate, 0.5 μM) blocks these changes. (From Boron WF, Boulpaep EL: Intracellular pH regulation in the renal proximal tubule of the salamander. Basolateral HCO3- transport. J Gen Physiol 81:53–94, 1983.)
The basolateral Na- HCO3- co-transporter has now been cloned (named NBC transporter for Na bicarbonate cotransporter) and found to be distantly related to the red cell Cl-/HCO3- exchanger AE1.   The basolateral NBC in the proximal tubule is the NBC1 isoform first cloned from the sala-mander Ambystoma and later from human. The human gene is designated SLC4A4. NBC1 (also called kNBC for kidney NBC) encodes a 1035 amino acids protein with predicted size of 116 kDa several potential phosphorylation sites, and 12 predicted membrane spanning segments. The NBC transporter in the late proximal tubule may not be NBC1. Other isoforms are known to be electroneutral.    All of the NBC are sensitive to inhibition by DIDS (4,4′-Diisothiocyanostilbene-2,2′-Disulfonic Acid), SITS, and other disulfonic stilbenes. The large family of HCO3- transporters also includes a K+/HCO3- cotransporter and a Na+-dependent Cl-/HCO3- exchanger. These features are discussed in more detail in another chapter.
Although the physiologic studies discussed earlier suggest that NBC-1 functions in a 3:1 HCO3-: Na+ mode, some experiments support that it can also operate in a 2:1 mode in certain circumstances.      These recent experiments suggest that cAMP through PKA phosphorylates the C-terminus of NBC1 and changes the stoichiometry to 2:1.    There may also be some interaction in this process with CA.
For the basolateral membrane, both Na+ dependent Cl-/HCO3- exchange     and Na+ independent Cl-/HCO3- exchange (in the S3 segment)    have also been found, but the role in transepithelial acid-base has not been established. Variable evidence exists for basolateral Na-H exchange in some proximal segments of some species   ; when present basolateral Na-H exchange would not function in transepithelial HCO3-reabsorption, but to regulate cell volume and pH as in other cells.
Citrate and other organic anions are also reabsorbed in the proximal tubule. Changes in their reabsorption and urinary excretion could alter acid-base balance in that these organics anions can be metabolized to HCO3- if reabsorbed. Thus, this reabsorption prevents the loss of excess “potential base” into the urine. In fact, in the rat, urinary excretion of citrate and other organic anions contributes substantially to the excretion of alkali, for instance in the recovery from metabolic alkalosis.     And urinary citrate and other organic anions increase in the urine with alkalosis, and decrease with acidosis. In humans, urinary citrate does change in the ap-propriate direction with acid-base changes—a decrease in excretion with acidosis or acid loads, and an increase in excretion with alkalosis or alkali loads, but the magnitude is usually sufficiently small (usually ≈5–10 mEq/day) that major influences on systemic acid-base balance are limited. Other organic acids and their anions, in particular lactate and acetate, have been shown to modulate intracellular pH, at least in salamander proximal tubules, and probably only in the absence of CO2 and HCO3-.   
The proximal tubule has high ionic permeabilities for H+ and HCO3-, and also for CO2 discussed earlier.    The high H+ permeability results in little H+ transport because of the low concentrations of free H+. The high CO2 permeability does allow rapid equilibration of CO2 in the adjacent structures of the kidney (e.g., tubule lumen, cell, and interstitium); see earlier discussion. The large paracellular HCO3- permeability limits net HCO3-reabsorption in the late proximal tubule (where luminal HCO3- concentration is low compared with peritubular concentrations) and hence allows greater delivery of HCO3- out of the proximal tubule. Therefore, because of this relatively large permeability of the proximal tubule to HCO3-159 and the thermodynamics of Na-H exchange, the proximal tubule is only able to lower the luminal pH to ≈6.7 and the luminal HCO3- to ≈7 μM to 8 μM.   (Regarding the thermodynamics, because the Na-H exchanger is a neutral exchanger driven by the Na gradient, which is ≈140 μM lumen: ≈10 μM to 20 μM cytoplasm or 10:1, the induced H+ gradient can theoretically only be ≈10:1 H+ concentration or 1 pH unit.) Therefore, the proximal tubule is a “high capacity, low gradient” system for H+/HCO3- transport in contrast to the distal nephron discussed later. Continued Na-H exchange, even when the luminal fluid has reached a plateau phase HCO3- level, is important however for net NaCl reabsorption.
Regulation of Proximal Tubule Acid-Base Transport
Acid-base transport in the proximal tubule is a complex process, responding in most circumstances to maintain acid-base homeostasis, but also responding to a variety of hormones that are not necessarily homeostatic for acid-base balance. For instance, in some disease states, these hormones may actually cause or perpetuate acid-base disorders. Metabolic alkalosis for example is often perpetuated by renal retention of HCO3- and urinary acid excretion; and the proximal tubule participates in this process. In the proximal tubule, HCO3- reabsorption may increase secondary to angiotensin II, increased filtered load of bicarbonate, decreased HCO3- backleak across the paracellular pathway, and potassium deletion—each discussed later.
Acid-Base Balance and Peritubular pH
In general, the proximal tubule responds to systemic acid-base changes (either frank acid-base disorders or acid or base loads) in a direction to restore acid-base balance. So, acidosis or acid loads increase proximal tubule H+secretion and HCO3- reabsorption, and alkalosis or base loads decrease H+ secretion and HCO3- reabsorption. The responses to acidosis or decreases in peritubular pH are complex, apparently involving a variety of both intrinsic mechanisms and systemic hormonal mechanisms. In addition, there are different mechanisms for acute and chronic responses to acid or base loads.
With decreases in peritubular pH (either increased pCO2 or decreased HCO3- concentration), proximal tubule HCO3- reabsorption increases; and the opposite occurs with increases in peritubular pH.         (There are some conflicting data on acute increases in CO2.   Also, the amount of HCO3- reabsorption in vivo will also depend on the filtered load and concentration of HCO3-, which may be reduced in metabolic acidosis.) Decreases in cell pH, which result from HCO3- exit on the Na-HCO3- cotransporter with decreases in basolateral HCO3-, stimulate apical H+ secretion via the apical Na-H exchanger. This will occur via kinetic effects with increased cell H+ concentrations, but intracellular acidosis also has an allosteric stimulation of the Na-H exchanger. This is illustrated in Figure 7-7 . An allosteric activation of Na-H exchange is a feature of most isoforms of NHE, and appears to depend on amino acid residues in the C terminus portion of the molecules. These changes occur immediately. There is also acute exocytic insertion of vesicles (probably containing both H+-ATPase and NHE-3) into the brush border apical membrane, at least with acidosis caused by increased CO2. As discussed later, NHE-3 exists associated with other proteins and in different domains of the apical region of the cell; the precise steps of exocytic insertion and retrieval are not known, but are being actively investigated.
FIGURE 7-7 Allosteric regulation of Na-H exchange in proximal tubule brush border membrane vesicles. Upper panel. Sodium influx as a function of intravesicular pH. The insert shows the same data expressed as a function of intravesicular H+ concentration, showing a non-linear (sloping upward) increase of Na transport with decreasing pH, increasing H+. Lower panel. Sodium efflux from vesicles at two intravesicular pH values. The remaining sodium content is plotted as a function of time in the presence and absence of amiloride at intravesicular pH values of 7.47 and 6.90. At the lower intravesicular pH, there is a greater rate of amiloride-sensitive sodium efflux. The effect of pH in this case can not be a substrate effect of more H+ for exchange with Na+. (From Aronson PS, Nee J, Suhm MA: Modifier role of internal H+ in activating the Na+-H+exchanger in renal microvillus membrane vesicles. Nature 299:161–163, 1982.)
Boron and colleagues have also demonstrated that H+ secretion in the proximal tubule is directly stimulated in response to basolateral CO2, apparently independent of pH; they have postulated that there is a “CO2 sensor” in the proximal tubule.     This CO2 sensor mechanism appears to interact with angiotensin II and to involve a tyrosine kinase.  
Over a more prolonged period of acidosis (days), a variety of other adaptive changes occur to increase HCO3- reabsorption even more.   With chronic acidosis, Na-H exchange in the brush border increases and Na-HCO3-co-transport in basolateral membranes increases, whether studied in cells or membrane vesicles.       The increase in basolateral Na-HCO3- co-transport with metabolic acidosis may result from post-translational modifications of NBC-1 because protein levels do not change. Some of the effects of acidosis (perhaps exocytic insertion) can occur in vitro, in as little time as two hours. Similar types of changes are seen with respiratory acidosis, and opposite changes with alkalosis    ; however, some investigators have not found the same results with respiratory acidosis.   With acidosis, there is an increase in NHE3 protein in the apical membrane brush border, but not an increase in NHE3 mRNA in vivo; there is, however, an increase in NHE-3 mRNA in the OKP cell culture model. The increase in NHE-3 protein in the apical membrane results predominantly from increased exocytic insertion from subapical membrane vesicles, but there may be increased protein translation as well.   
Hormones also play a critical role in the response to acidosis. These include endothelin-1 (ET-1), glucocorticoids, and possibly PTH. With acidosis, increases in renal endothelin-1   and cortisol from the adrenal occur and may play significant roles (see later discussion). Alpern and colleagues have proposed and experimentally supported the elegant scheme illustrated in Figure 7-8 whereby endothelin is an integral autocrine or paracrine component of the mechanism whereby acidosis causes adaptation in NHE-3. These aspects are presented later in the section on endothelin. In sum, the response to acidosis is complex, involving multiple steps and separate mechanisms. Key elements are turning out to be intrinsic allosteric responses of NHE-3, hormonal responses that secondarily up-regulate Na-H exchange, and exocytic insertion of NHE-3.
FIGURE 7-8 Signal transduction mechanism of acidosis-induced adaptation of Na-H exchange proposed by Alpern and colleagues. (Adapted from Laghmani K, Preisig PA, Alpern RJ: The role of endothelin in proximal tubule proton secretion and the adaptation to a chronic metabolic acidosis. J Nephrol 15 Suppl 5:S75–S87, 2002.)
Potassium depletion also increases proximal tubule HCO3- reabsorption. There is an increase in both the apical Na-H exchanger and the basolateral Na-HCO3- co-transporter. These changes may result in large part from low potassium inducing an intracellular acidosis and resulting adaptive changes in the transporters.  
Extracellular Volume, luminal Flow Rate, and Delivery of HCO3-
Increases in luminal HCO3- concentration, usually accompanied by increased luminal pH, increase proximal HCO3- reabsorption.   This increased reabsorption is due to an increased rate of H+ secretion by the apical Na-H exchanger, probably due to positive kinetic effects of decreases in the luminal H+ concentration.     As Na-H exchange increases, cell pH will rise and stimulate basolateral Na-HCO3- co-transport out of the cell. Alpern   has noted that this HCO3- concentration effect will attenuate the effects of other influences on HCO3- reabsorption. For instance, if a hormone stimulates HCO3- reabsorption, this will decrease luminal HCO3-concentration, which will in turn secondarily decrease HCO3- reabsorption, attenuating the original change.
Increasing luminal flow also increases proximal tubule HCO3- reabsorption. This occurs both by increases in mean luminal HCO3- concentration, which will have effects as discussed earlier and by a direct effect of flow rate on Na-H exchange.    This effect of flow rate on the apical Na-H exchanger appears to be a direct effect, possibly on an apical diffusion barrier. Chronic changes in luminal flow rate in vivo (induced experimentally by hyperfiltration from uninephrectomy, renal mass reduction, or high protein diets) cause additional long-term adaptive increases in both the apical Na-H exchanger and the basolateral Na-HCO3- co-transporter.     An important consequence of increasing proximal HCO3- reabsorption with increasing delivery (glomerulotubular balance for HCO3-) is prevention of excessive delivery downstream and urinary excretion.
Volume expansion usually leads to a reduction in proximal HCO3- reabsorption.     This is in spite of the fact that extracellular volume expansion may increase GFR, filtered HCO3-, and luminal flow, factors discussed earlier that could increase proximal HCO3- reabsorption. Part of the effect of volume expansion to decrease HCO3- reabsorption is via increased HCO3-permeability, but part is due to an effect on H+ secretion.PTH may also be involved in this process. Hypertension, and the often associated natriuresis, has been associated with a redistribution of NHE-3 in the proximal tubule also.    In contrast, volume contraction or low dietary sodium is often accompanied by increased proximal tubule HCO3- reabsorption. This may be secondary to angiotensin II, catecholamines, or dopamine causing changes in Na-H exchange.
A variety of hormones modulate proximal tubule acid-base transport. Some of these effects are involved in the response to acidosis and alkalosis as discussed earlier, but others are not involved in acid-base homeostasis, and the acid-base effects appear collateral.
Endothelin-1 (ET-1), acting on the ETB receptor in proximal tubules, may be a critical factor in the response to acidosis as discussed above and illustrated in Figure 7-8 .   Renal ET-1 is produced in response to acidosis,    and its effects on the ETB receptor are critical in the NHE-3 response to acidosis. Acidosis, and decreases in intracellular pH, increase ET-1 synthesis in the kidney, specifically by microvascular endothelial cells and proximal tubule cells.    ET-1 in low concentrations (10-13 M) increases proximal tubule reabsorption; high concentrations inhibit reabsorption. Both apical Na-H exchange as well as basolateral Na-HCO3-cotransport increase with low concentrations of ET-1.   The ETB receptor is responsible for these acid-base effects.   ETB activation leads to phosphorylation of NHE-3 and its insertion in the apical membrane.      In ETB receptor deficient mice, acid ingestion does not lead to normal apical insertion of NHE-3 and ET-1 does not lead to increased Na-H exchange activity; however, there is normal urinary excretion of titratable acid and NH4+. Distal tubule effects of ET-1 are discussed later. The signal transduction mechanisms whereby acidosis and/or low intracellular pH stimulate ET-1 synthesis has been extensively studied by Alpern's group in cultured proximal tubule cells (OKP), and to a lesser extent in vivo; the mechanism appears to involve sequential activation of Pyk2 (a non-receptor tyrosine kinase), c-Src (another non-receptor tyrosine kinase), followed by ERK activation, and c-fos/c-jun (immediate early genes) activating the AP-1 promoter site of the ET-1 gene.      ET-1 stimulation leads to a calcium and tyrosine kinase dependent phosphorylation, membrane insertion, and hence activation of NHE-3; other proteins such as paxillin and p125FAK are phosphorylated in this process as well.      Similar signaling pathways have been implicated in the stimulation of basolateral Na-HCO3- co-transport.  
Glucocorticoids also are an important component of the response to metabolic acidosis.   Metabolic acidosis increases cortisol, which is necessary for the increase in Na-H exchange activity in response to metabolic acidosis. Glucocorticoids increase Na-H exchange by multiple steps, but importantly include an increased translation and insertion of NHE-3 protein into the apical membrane.     Cortisol may also increase NHE-3 mRNA. Glucocorticoids increase NBC1 mRNA levels and activity in the proximal tubule.   Therefore, glucocorticoids appear to be a parallel and perhaps synergistic pathway with ET-1/ETB in the response to acidosis. Glucocorticoids also stimulate ammonium excretion, discussed later. Thus, glucocorticoids represent one of the hormone systems that integrate the response to acidosis. Glucocorticoids are also important in the development and maturation of proximal tubule transport.
Parathyroid hormone (PTH) acutely decreases proximal HCO3- reabsorption via increases in cAMP.    PTH increases cAMP, which activates PKA. PTH via PKA immediately phosphorylates NHE-3 and inhibits activity, and over a slightly longer time frame NHE-3 undergoes phosphorylation-dependent endocytosis.     This endocytosis is microtubule and dynamin dependent. NHERF, Na-H exchange regulatory factor discussed later, may also be involved. PTH also inhibits basolateral Na-HCO3- co-transport.   NHERF is necessary for this inhibition of Na-HCO3- co-transport.  
The chronic effects of PTH may differ substantially. PTH levels rise in metabolic acidosis and may be important in the ultimate adaptive increase in net acid excretion (both TA and ammonium). Although there may be a transient increase in urinary HCO3-, PTH effects on the loop of Henle and distal nephron are to increase acid excretion.    Consistent with an adaptive chronic role of PTH via stimulating cAMP, on a chronic basis cAMP (and hormones that stimulate cAMP) may actually increase Na-H exchange. The acute hormonal regulation of NHE-3 is a complex mechanism that is an intense area of investigation; this area is discussed more later and has recently been reviewed thoroughly.
Angiotensin II increases HCO3- reabsorption by increases in apical H+ secretion and basolateral HCO3- transport. Angiotensin II produced by the proximal tubule may stimulate luminal receptors to stimulate HCO3-reabsorption. Angiotensin II increases exocytic insertion and activity of NHE3.    Basolateral Na-HCO3- transport is also directly stimulated.   The mechanisms of these responses include decreased cAMP, activation of protein kinase C, and activation of tyrosine kinase (src)/MAPK pathways.    
Other hormones also can regulate proximal tubule acid-base transport, but in some cases the physiologic and pathophysiologic implications are not well understood. Insulin, dopamine,    thyroid hormone,glucagon, adenosine,   cholinergic agents,   and others modulate proximal tubule HCO3- transport. For instance, dopamine modulates apical Na-H exchange and this has anticipated effects on sodium balance, but particular systemic acid-base changes are not known. Catecholamines stimulate HCO3- reabsorption.   α-2 receptors activate NHE-3 by interacting with NHERF (Na-H exchanger regulatory factor) discussed later. Activation of adenosine A1 receptor inhibits NHE-3 via a PKC and phospholipase C mechanism involving calcineurin homologous protein interaction. Neuronal and inducible nitricoxide synthase also modulate HCO3-reabsorption.  
Common Acute Signal Transduction Mechanisms
Several hormones and perhaps other signals share some common acute signal transduction mechanisms in the proximal tubule. A number of hormones such as PTH and catecholamines (in addition to angiotensin II discussed earlier) function at least in large part via changes in cAMP and protein kinase A (PKA). As recently reviewed thoroughly by Moe, phosphorylation of the carboxy-terminal domain of NHE-3 and endocytosis of NHE-3 appear to be key events. The exact mechanism whereby phosphorylation leads to decreased activity is still being investigated; both endocytosis and intrinsic changes in NHE-3 may be involved, and co-factors discussed later are likely necessary. Trafficking of NHE-3 between the apical membrane and other compartments is also a common theme (see discussion of acidosis, PTH, endothelin). In addition to NHE-3 phosphorylation by PKA, endocytosis can also be regulated by a phosphatidylinositol 3′ kinase-dependent pathways.
NHERF (also known as EBP50) is a protein cofactor that is important for cAMP mediated regulation of NHE-3 activity.    NHERF, a 55 kD phosphoprotein with two PDZ domains, links ezrin, NHE-3, and PKA to the actin cytoskeleton.   This linkage allows NHE-3 phosphorylation and inactivation.     NHERF may also regulate basolateral Na-HCO3- co-transport.   The α2-adrenergic receptor can directly associate with NHERF through its PDZ domain, providing a mechanism of regulation of NHE-3 activity. Reorganization of the cytoskeleton may also be involved in inactivation of NHE-3 by cAMP. The PDZ-based adaptor Shank2 is another protein likely involved in trafficking of NHE-3.
Linkage of NHE-3 to megalin may also be important. Recent studies demonstrated that NHE-3 exists as both 9.6 and 21 S oligomers in the renal brush border.   The lighter fraction localizes to the microvilli, not associated with megalin, and is functionally active. The denser fraction contains NHE-3 associated with megalin in the intermicrovillar region of the brush border and is not active. Shifting of NHE-3 between these two fractions and domains may be an important mechanism of acute regulation.  
LOOP OF HENLE AND THICK ASCENDING LIMB
The loop of Henle (including the thick ascending limb, TAL) reabsorbs much of the HCO3- that leaves the proximal tubule (see Fig. 7-1 ); this represents 10% to 20% of the total filtered HCO3-.    The amount of HCO3- reabsorbed in vivo in the loop of Henle has been determined using micropuncture to measure the HCO3- delivery to the end of the superficial proximal tubule and to the early distal tubule, see Figure 7-1 . Between these two sites, several distinct nephron segments exist: the late proximal tubule, the thin descending and ascending limbs, and the medullary and cortical TAL. Probably only the late proximal tubule and the thick ascending limbs account for the active HCO3- reabsorption and most of this HCO3- reabsorption probably occurs in the TAL as discussed in detail later.   The amount of HCO3- reabsorbed by the late proximal tubule in vivo is relatively small. This is probably due to limited amount of delivered HCO3- from the early proximal tubule and a limited intrinsic capacity of this segment to reabsorb HCO3-. This is supported by in vivo studies, which indicate that fractional delivery (FD) of HCO3- at the late superficial proximal tubule is minimally different from that at the bend of the loop of Henle (see Fig. 7-1 ). However these data are complicated by the fact that measurements in the loop of Henle are derived from deep (or juxtamedullary nephrons) whereas measurements in the late proximal tubule are drawn from outer cortical nephrons. Importantly, in the descending loop of Henle, the luminal HCO3-concentration rises toward the bend of the loop of Henle as water is abstracted with minimal HCO3- reabsorption (see Fig. 7-1 ). Subsequently, reabsorption of HCO3- in the TAL is resumed, which lowers luminal HCO3- before the start of the distal tubule. As will be discussed, HCO3- reabsorption in the TAL is concentration dependent and therefore the rise in luminal HCO3- concentration before this segment is physiologically important.
The general features of HCO3- reabsorption in the thick ascending limb are shown in Figure 7-9 . Although specific properties may differ between cortical and medullary TAL (and among experimental species) HCO3- reabsorption, like in other segments, is dependent on luminal H+ secretion and basolateral efflux of HCO3-. As expected, HCO3- reabsorption in the TAL can be inhibited by CA inhibitors.   Apical Na-H exchange mediates most, if not all, of H+ secretion in the TAL. This has been demonstrated by in vitro and in vivo inhibitor and ion substition experiments.    NHE-3 is likely the dominant isoform; NHE-3 has been demonstrated by immunohistochemical studies and specific functional inhibitor studies.     NHE-2 is present in the apical membrane, and could be functionally active. Na-H exchange in the TAL is usually relatively pH independent and is inhibited by hyperosmolality in contrast to other epithelia.   H-ATPase is present in the apical membrane of the TAL, and some HCO3- reabsorption in the loop is sensitive to bafilomycin, although some of this could be late proximal tubule sensitivity. Because HCO3- reabsorption in the TAL in vitro is predominantly Na dependent, a major role for H+-ATPase in HCO3- reabsorption is unlikely. A K+-dependent HCO3- transport pathway, possibly a K+-HCO3- cotransporter was also identified in the apical membrane of medullary TAL. This mechanism, driven by a large cell to lumen K+ concentration gradient, opposes transepithelial HCO3- reabsorption. The molecular identity and physiological role of this mechanism are not yet clear.
FIGURE 7-9 Model of acid-base transporters in the thick ascending limb. See text for details. (Adapted from Hamm LL, Alpern RJ: Cellular mechanisms of renal tubular acidification. In Seldin DW, Giebisch G (eds): The Kidney: Physiology and Pathophysiology. Philadelphia, Lippincott Williams & Wilkins, 2000, pp 1935-1979.)
Renal excretion of NH4+ plays a very important role in renal acid base transport. In the TAL, NH4+ is predominantly reabsorbed, which is counter to what is expected if acid is to be excreted. Yet reabsorption of NH4+ by the TAL is necessary for establishing a medullary high concentration of NH4+ that is needed for regulating acid secretion into the collecting duct. In general, NH4+ is transported in the TAL by substituting for K+, which it resembles in size and charge. The apical mechanisms responsible for reabsorbing NH4+ include Na+/K/2Cl- and K+ channels. Other mechanisms include a K/H exchanger and Na+-H exchange. Transport of NH4+ is discussed in details in a later section.
Na-HCO3- co-transport at the basolateral membrane may mediate HCO3- transport into the peritubular fluid from the TAL cell. Electroneutral NBC 2 (also known as NBCn1) is thought to be the predominate isoform, at least in the medullary portion of the TAL.   But, basolateral Cl-/HCO3- exchange and K-HCO3- transport are present and may be important mediators of transepithelial HCO3- transport.      AE2 (anion exchanger 2) is present in abundance in the TAL   and may mediate some of the adaptive changes that occur in acid-base transport.   A basolateral Na-H exchanger, NHE-1 and probably NHE-4, is also present and likely functions in part to regulate apical Na-H exchange, as discussed later.    The specific role of each of these multiple transporters is not clear, but might be important in independently regulating the transport of specific solutes (and simultaneously cell pH and volume) in a segment in which Na+, Cl-, HCO3-, and ammonium are reabsorbed in single cell types.
Regulation of HCO3- Transport in the Thick Ascending Limb
Systemic acid-base balance, particularly metabolic acidosis, regulates HCO3- reabsorption in the loop of Henle and thick ascending limb.   NHE-3 and basolateral Na-HCO3- co-transport increase in response to acidosis.  Similar adaptations occur for NH4+ transport as discussed later. In contrast, as metabolic alkalosis and respiratory acid base disturbances do not cause major changes in HCO3- transport in the TAL.   This apparent lack of adaptation may result from opposing influences of the acid-base status and sodium delivery (discussed later) in the experimental models studied. NHE-3 does change with metabolic alkalosis.
Thick ascending limb HCO3- reabsorption increases as luminal HCO3- concentration increases.   Therefore, the increasing concentration of HCO3- in the descending loop of Henle as H2O is reabsorbed is physiologically important for TAL HCO3- reabsorption. As shown in Figure 7-1 , the concentration of HCO3- delivered to the TAL is above 20 μM, significantly greater than the ≈7 μM to 10 μM concentration at the end of the proximal tubule.
Changes in dietary sodium and a variety of hormones also modulate loop and TAL HCO3- transport. Increases in dietary sodium increase loop and TAL HCO3- reabsorption measured in vivo and in vitro respectively.  Although prior studies had suggested that aldosterone might increase TAL HCO3- transport, recent studies reported that aldosterone inhibits TAL HCO3- reabsorption by a non-genomic mechanism inhibition of NHE3 action.  Therefore, the effects of dietary sodium could be secondary to changes in aldosterone because aldosterone would be suppressed with high dietary sodium. In contrast, physiologic doses of glucocorticoids, or supraphysiologic doses of aldosterone, restore loop of Henle HCO3- reabsorption after adrenalectomy. Changes in NHE-3 expression do not appear to be responsible for the effects of dietary sodium.
A variety of other hormones alter TAL HCO3- transport: angiotensin II, nerve growth factor, prostaglandin PGE2, PTH, and glucagon. Angiotensin II inhibits TAL HCO3- reabsorption in contrast to its effects in the proximal tubule. The physiologic importance of these hormonal effects has not been clearly delineated yet. PTH increases loop acid secretion, which has been proposed to be an important component of the response to acidosis.   The role of changes in HCO3- transport in the TAL are difficult to determine in vivo because of the large amount of bicarbonate reabsorption upstream in the proximal nephron and the final regulation of urine acidification in the collecting duct. The signaling pathways for regulation of TAL HCO3- transport are diverse: extracellular signal-regulated kinase (ERK), cytochrome P-450, and phosphatidylinositol 3-kinase (PI3-K), and the cAMP pathway.      
A novel mechanism of regulation of TAL HCO3- transport is regulation of apical Na-H exchange by basolateral Na-H exchange.   NHE1 is proposed to control activity of NHE3, and consequently HCO3- reabsorption, by a mechanism involving a change in cellular polymerized actin. Both NHE-1 and NHE-4 are likely present in the basolateral membrane of the TAL.   
Hyper- and hypo-osmolality also affect HCO3- transport in the TAL.     Hypertonicity inhibits HCO3- reabsorption and hypotonicity stimulates HCO3- reabsorption. These actions depend on a tyrosine kinase dependent pathway. ADH, which will lead to medullary hypertonicity, also directly reduces TAL HCO3- reabsorption.    Loop diuretics stimulate TAL HCO3- reabsorption, possibly via increases in cell sodium, but also possibly secondary to medullary hypotonicity.  
The distal nephron is responsible for the final regulation of acid excretion. To accomplish this, the distal nephron reabsorbs the remaining filtered bicarbonate, generates titratable acid, and “traps” NH4+ for excretion into the final urine.   All of these functions result from H+ secretion just as in the preceding nephron segments. The distal nephron does have a limited capacity for H+ secretion and normally reabsorbs only ≈5% to 10% of the filtered HCO3-.
The distal nephron is composed of several distinct segments including the distal convoluted tubule, the connecting segment, the cortical collecting duct, the medullary collecting duct (outer and inner stripe portions), and the inner medullary collecting duct (with initial and terminal portions). Some of these segments also have multiple cell types. Despite these different cell types, several segments share features of acid secretion, depicted in Figure 7-10 . The differences between segments will be detailed later. The cell model in Figure 7-10 is derived mostly from work in the type A or a intercalated cells (IC) in the cortical collecting duct (CCD), and from prior studies in the turtle bladder model epithelium,   but similar mechanisms exist in most acid secreting cells of the distal nephron. (Types A and B IC are sometimes used to only indicate rat cells, whereas a and b are used for rabbit IC cells; here, A and B refer to any experimental species.) The turtle bladder, an ancestral and embryologic relative of the collecting tubule, was used extensively in the past as an in vitro model of distal nephron acid-base transport and established many of the mechanisms now accepted in mammalian distal nephron.   These studies established that active, electrogenic H+ secretion, independent of other ions and HCO3-, mediates apical acidification. (One study suggested primary base absorption in the turtle bladder, but this has not been confirmed.) In the CCD, type A IC are the prototypical acid secreting cells interspersed among more numerous principal cells. The principal cells are responsible for most of Na+, K+, and H2O transport. A vacuolar-type H+ ATPase mediates much of the H+ secretion by the type A IC. A Cl-/HCO3- exchanger, anion exchanger 1 or AE1 (also called band 3 protein), on the basolateral membrane mediates HCO3- extrusion into the interstitium and peritubular blood. Another H+ pump, H-K-ATPase (probably of at least two types discussed later), is also important for H+ secretion, at least with some conditions such as K+ deficiency. An apical Na-H exchanger (NHE-2) also secretes H+ in the distal convoluted tubule and connecting segment.   
FIGURE 7-10 Model of acid-base transport in the H+ secreting type A intercalated cells of the cortical collecting duct. See text for details. (Adapted from Hamm LL, Alpern RJ: Cellular mechanisms of renal tubular acidification. In Seldin DW, Giebisch G (eds): The Kidney: Physiology and Pathophysiology. Philadelphia, Lippincott Williams & Wilkins, 2000, pp 1935-1979.)
A unique feature of acid-base transport in the distal nephron is HCO3- secretion; this occurs by type B or b intercalated cells in the CCD and connecting tubule, discussed later. The general mechanism of HCO3- secretion is modeled in Figure 7-11 and discussed in detail later. HCO3- secretion is electroneutral, independent of Na+, and coupled to Cl- reabsorption. The driving force for HCO3- secretion is likely basolateral H+ATPase as discussed later, with apical HCO3- transport occurring via an apical chloride bicarbonate exchanger. This apical exchanger is likely pendrin, discussed later. Bicarbonate secretion was originally described in CCD from alkali loaded rabbits, but was subsequently shown in the superficial distal nephron and CCD of rats, and in CCD of mice.     Metabolic alkalosis (and recovery from metabolic alkalosis), mineralocorticoids (possibly via metabolic alkalosis), and isoproterenol stimulate HCO3- secretion     ; and acid loads inhibit HCO3- secretion.   (The time frame over which HCO3- secretion is stimulated in metabolic alkalosis has not been studied in detail and may depend on the experimental model used.) The process of HCO3- secretion occurs simultaneously with H+ secretion by a separate cell type (see discussion of interconversion of cell types later)   ; whether net HCO3- reabsorption or secretion occurs depends on the relative magnitude of the two processes in the CCD and distal tubule.
FIGURE 7-11 Model of HCO3- secreting type B intercalated cells of the cortical collecting duct. See text for details. (Adapted from Hamm LL, Alpern RJ: Cellular mechanisms of renal tubular acidification. In Seldin DW, Giebisch G (eds): The Kidney: Physiology and Pathophysiology. Philadelphia, Lippincott Williams & Wilkins, 2000, pp 1935-1979.)
Both type A and B IC cells in the distal nephron have abundant cytoplasmic carbonic anhydrase as discussed earlier. In contrast, functional luminal membrane bound carbonic anhydrase is present in only a minority of cells along the distal nephron.
Although these general models of acid-base transport pertain to several acid-base transporting cells along the distal nephron, there are differences among the various segments and between experimental species. These differences will be discussed later. The unique characteristics of each segment have been studied with different techniques (e.g., in vivo micropuncture, microperfusion, cell culture) because of the relative inaccessibility of each segment.
Distinct Features of Specific Distal Tubule Segments
Micropuncture studies of rats usually define the distal tubule as beginning after the macula densa and extending to the first junction with another tubule. Defined this way, the distal tubule includes four distinct morphologic segments: a short segment of the TAL, the distal convoluted tubule, the connecting segment, and the initial collecting tubule (see Chapter 1 ). However, the exact morphology depends on species; and function has essentially only been examined in rats, with few exceptions. Micropuncture studies in rats have clearly shown H+ secretion (or HCO3- reabsorption) in the superficial distal tubule of the rat.         Although both the early and late distal tubule secrete H+, only the more distal aspects of the superficial distal nephron (connecting tubule) have intercalated cells. The early superficial distal nephron (predominantly distal convoluted tubule) secretes H+ via both an apical Na-H exchanger (likely NHE-2) and H+ ATP.    The late superficial distal tubule (connecting segment and initial collecting duct) secretes H+ via a H+ ATPase, and probably H+-K+-ATPase. The colonic isoform of H-K-ATPase is particularly prominent in the apical membranes of some cells of the connecting segment and early CCD.  
The late superficial distal tubule (and connecting segment specifically) also secretes HCO3- with alkali loading.      Net HCO3- transport (the sum of secretion and reabsorption) varies with diet, acid loading, and other conditioning in vivo and also with luminal flow rate. Studies using variations in luminal Cl- demonstrate that both HCO3- reabsorption and HCO3- secretion are present in the late distal tubule, just as in the cortical collecting duct described in the next section.  
Cortical Collecting Duct (CCD)
The CCD has been the most studied of the distal nephron segments in vitro, and findings in these cells have been used to extrapolate to other distal nephron segments. In a pivotal group of studies, McKinney, Burg, and colleagues demonstrated that the rabbit CCD in vitro can either reabsorb or secrete HCO3-, depending on the acid-base conditioning of the animals.    These studies were later extended to the rat CCD.    As implied earlier, many studies suggest that HCO3- reabsorption (H+ secretion) and HCO3- secretion are separate processes mediated by distinct cell types, type A and B IC as in Figures 7-10 and 7-11  .
Most CCD from untreated normal rabbits secrete HCO3- when studied in vitro     ; in contrast, most CCD from untreated rats reabsorb HCO3-.   Simultaneous processes of HCO3- secretion and reabsorption are probably occurring in separate IC types in both species. The existence of two distinct, opposing processes has been inferred from HCO3- flux studies that selectively inhibit HCO3- reabsorption (with removal of luminal HCO3- or peritubular Cl-) or alternatively inhibit HCO3- secretion (with removal of luminal Cl- or basolateral HCO3-).    HCO3- reabsorption is also blocked by disulfonic stilbenes such as SITS and DIDS added to the basolateral aspect.   HCO3- secretion is not inhibited by luminal addition of stilbenes as discussed later. Simultaneous HCO3- secretion and H+ secretion was also demonstrated in rabbit CCD by measuring an acid disequilibrium pH in CCD with net HCO3- secretion.
H+ secretion (often measured as HCO3- reabsorption) has actually been studied most clearly in outer medullary collecting ducts in which no HCO3- secretion occurs; H+ secretion in the CCD is thought to have the same mechanisms. H+ secretion in both outer medullary collecting duct (OMCD) and CCD is electrogenic (lumen-positive transepithelial voltage with inhibition of Na+ transport) and sodium-independent.   CCD HCO3-secretion is electroneutral, Na+- independent, and coupled to Cl- absorption.     Both reabsorption and secretion of HCO3- are inhibited by acetazolamide. Acid loads in vivo increase net HCO3- reabsorption in the CCD. However, the predominant effect of acid loads is inhibition of unidirectional HCO3- secretion, with a smaller effect of stimulation of unidirectional HCO3- reabsorption.       HCO3- secretion is increased by mineralocorticoids given in vivo (at least in alkalotic animals). CCD H+ secretion may also be increased by mineralocorticoids, both by direct stimulation and by stimulation of Na+ transport and a lumen negative transepithelial voltage.
The existence of separate functional and morphologic IC types is again analogous to findings in the turtle urinary bladder. The rat CCD has at least two distinct morphologic types of IC, both containing carbonic anhydrase.    The type A cell has a mixture of apical microplicae and microvilli, apical intramembranous rod-shaped particles (which are associated with H-ATPase as described later), apical immunoreactivity for H-ATPase, and basolateral AE-1 (or band 3 protein).     In contrast, type B IC have few apical microvilli, H-ATPase, and rod-shaped particles on the basolateral membrane, but no AE1.      Pendrin is also located on the apical membranes of rat (and mouse) type B IC   (see Figs. 7-10 to 7-13    ). In the rabbit CCD, which has been studied more functionally, IC do not separate as clearly into types based on morphology.All rabbit CCD ICs contain both apical and basolateral rod-shaped particles, although to varying extent. Rabbit ICs, however, are functionally distinct and have distinct polarization of certain transport proteins. Type A IC from rabbit CCD have apical H-ATPase and basolateral AE-1.   As expected with basolateral Cl-/HCO3- exchange, type A IC alkalinize on removal of basolateral Cl-.   These cells also exhibit endocytosis of luminal fluorescent macromolecules, presumably reflecting in part recycling of apical membrane H-ATPase as discussed later.    type A IC in the rabbit CCD are relatively infrequent in the outer cortex, but become more abundant toward the medulla.   Type B (or HCO3- secreting) IC from rabbit, the predominant IC type in the outer cortex, have expected rapid changes in intracellular pH (pHi) with changes in luminal Cl- or HCO3-, and cell acidification on removal of basolateral Cl-. These cells can be identified by apical labeling with peanut lectin.     Rabbit B IC (peanut lectin positive) usually have diffuse staining for H-ATPase, rather than basolateral staining as in the rat type B IC. ICs also express H,K-ATPase as discussed later.    Both A and B ICs have basolateral Cl- channels and basolateral Na-H exchange to regulate intracellular pH.   
FIGURE 7-12 Illustration of AE-1 and H-ATPase distribution in cells of the CCD. A, Cryostained section showing CCD from rat with acute metabolic alkalosis immunostained with monoclonal antibody to H+-ATPase. Basolateral H+-ATPase staining of type B IC is shown by arrowhead. Closed arrow indicates type A with apical H+-ATPase. B, CCD taken from rat with acute metabolic acidosis, immunostained with polyclonal antibody to AE1. Basolateral AE1 staining of type A IC is shown with closed arrow. Arrowhead indicates type B IC with no AE1 staining. (From Sabolic I, Brown D, Gluck SL, Alper SL: Regulation of AE1 anion exchanger and H(+)-ATPase in rat cortex by acute metabolic acidosis and alkalosis. Kidney Int 51:125–137, 1997.)
FIGURE 7-13 Demonstration of H-ATPase in both apical membrane and subapical vesicles of intercalated cell. High magnification transmission electron micrograph of the apical region of an intercalated cell from rat OMCD labeled for H+-ATPase using immunogold cytochemistry. Gold particles (black dots) label numerous apical membrane vesicles as well as the apical plasma membrane. (From Verlander JW, Madsen KM, Tisher CC: Structural and functional features of proton and bicarbonate transport in the rat collecting duct. Semin Nephrol 11:465–477, 1991.)
Besides type A and B IC, other types or intermediate phenotypes have been demonstrated. Some H+ secreting IC do not exhibit luminal endocytosis, a property of prototypical type A IC. Also, other ICs, sometimes referred to as rat G or rabbit γ or also as “non-A, non-B” IC, have been defined by studies of intracellular pH or atypical labeling by various antibodies.   Non-A, non-B IC are also seen in the mouse. In the studies of intracellular pH, these cells are typically identified by both apical and basolateral Cl-/HCO3- exchange; these cells typically bind peanut lectin on the apical membrane. Other cells have apical H-ATPase, but no basolateral AE1. The exact morphologic characteristics, functional features, and adaptive responses for these atypical cells have not been clarified. The conjecture that these cells represent a versatile cell type, able to respond to acid or base loads, remains unproved, but as discussed later there is growing evidence for significant functional modification of some CCD ICs with acid loads.    Perhaps corresponding to the diversity and spectrum of cell types, studies of the cellular distribution of H-ATPase in rat CCD and OMCD show a range of staining patterns: from predominantly apical location, to predominantly cytoplasmic, to predominantly basolateral, depending on the acid-base status of the animal.
The IC are interspersed between more numerous principal cells (PC, ∼⅓ of CCD cells) which mediate sodium, water, and most of potassium transport under normal conditions. Although PC have several acid-base transporters on the basolateral membrane: Na-H exchanger, Na+- independent Cl-/HCO3- exchanger, and Na/HCO3- cotransporter,    these cells are not likely involved in transepithelial acid-base transport under normal conditions. As in many cells, these transporters in PC probably function to regulate pHi. No apical membrane acid-base transporters have been shown in PC.   Also, immunocytochemical and electron microscopy studies do not show H-ATPase, AE-1, pendrin, or significant H-K-ATPase.      Therefore PC (and the analogous granular cells of the turtle bladder) are not normally involved in transepithelial acid-base transport.
Therefore, different types of ICs mediate acid-base transport in the CCD, with separate processes of HCO3- reabsorption and HCO3- secretion, occurring in separate cell types. The specific transporters mediating these processes and the regulation are discussed later.
Outer Medullary Collecting Duct (OMCD)
The OMCD differs from the CCD in that this segment only reabsorbs HCO3-; HCO3- secretion has not been found.    For this reason, many studies have used this segment to better identify mechanisms of H+ secretion. OMCD HCO3- reabsorption is Na independent and coupled to basolateral Cl-/HCO3- exchange.    In contrast to the CCD, HCO3- reabsorption is relatively insensitive to inhibition by carbonic anhydrase. ICs constitute ⅓ of the OMCD cells in the rat. In the rabbit, the outer most part, the “outer stripe” (OMCDos), has ICs, but the inner stripe portion (OMCDis) has predominantly cells that differ morphologically from both PCs and ICs and have been termed “inner stripe cells”.   Although, only some OMCDis cells stain for apical H-ATPase and basolateral AE-1, all have at least some apical intramembranous rod-shaped particles associated with H-ATPase.    The OMCDis does not reabsorb Na+, and has a lumen positive transepithelial voltage from H+ secretion.
The H+ secreting ICs of the OMCD are similar in almost all respects to the type A ICs of the CCD described earlier and represented in Figure 7-10 : apical or cytoplasmic H-ATPase, Na-independent H+ extrusion sensitive to NEM, basolateral AE-1, basolateral Cl-/HCO3- exchange, H-K-ATPase, and no peanut lectin binding.          H-K-ATPase mediates significant HCO3- reabsorption in the OMCDis, particularly in potassium depleted rabbits.    OMCDis intercalated cells also have an apical electroneutral EIPA-sensitive, DIDS-insensitive Na-HCO3- cotransporter (NBC3) that functions predominantly in intracellular pH homeostasis. As with many epithelial cells, these cells express basolateral Na-H exchange, probably functioning to regulate intracellular pH rather than to participate in transepithelial acid-base transport. The electrophysiologic properties of both PCs and ICs have been characterized. ICs have a Cl- selective basolateral membrane, and virtually no measurable ionic conductance across the apical membrane.
In contrast to the most segments of the distal nephron, the rabbit OMCDis has functional luminal carbonic anhydrase, indicated by the lack of an acid luminal disequilibrium pH. This may facilitate a higher rate of HCO3-reabsorption.
Inner Medullary Collecting Duct (IMCD)
Morphologically and functionally, the IMCD has initial (first ∼⅓ of IMCD) and terminal segments, IMCDi and IMCDt respectively (see Chapter 1 ).   The rat IMCDi contains ∼10% ICs; but in the rabbit, the cells of the IMCDi are more homogeneous and resemble the inner stripe cells discussed earlier. The IMCDt cells are homogeneous without ICs and are referred to as IMCD cells.   The IC of the IMCD are similar to the IC of prior segments. Although the cells of the IMCDi have apical rod-shaped particles and membrane-associated CA, the IMCDt does not have these characteristics and yet secretes H+.   Immunoreactivity for H-ATPase, AE1, and H-K-ATPase has usually been demonstrated in only IC of the IMCD, but may be present in lower density in other cells based on functional studies discussed later.
The IMCD has been studied in the rat in vivo with micropuncture and micro-catheterization techniques.   The IMCD has luminal acidification, sodium-independent HCO3- reabsorption, and an acid disequilibrium pH (at least during systemic bicarbonate infusion).          Limited in vitro microperfusion studies of acid-base transport in the IMCD have been reported. Although, earlier studies found no luminal acidification in the rabbit IMCD, Wall and colleagues found low rates of H+ secretion and HCO3- reabsorption in the rat IMCD (both IMCDi and IMCDt) perfused in vitro.   Similar to the OMCDis, the IMCDi has functional luminal CA; this is not found in IMCDt.
However, there have been a relatively large number of cell culture and cell suspension studies of IMCD cells. These studies demonstrate both Na+-dependent and Na+-independent H+ transport.           H-ATPase clearly mediates H+ secretion in cultured IMCD cells.   NEM-sensitive ATPase activity (ascribed to H-ATPase) is found in the IMCDi.   However, as discussed later, H-K-ATPase also participates in H+ secretion as demonstrated by both cell culture and intact tubule studies.   As discussed for other collecting duct cells, a basolateral Na-H exchanger functions in pHi regulation, not likely in transepithelial transport.   Basolateral Cl-/HCO3- in the IMCD is likely mediated by AE1 and AE2.    Basolateral Na-coupled HCO3- transport has also been found in IMCD cells. In sum, the IMCD clearly secretes acid and participates in the regulation of final acidification, but the exact cellular localization of many key acid-base transport proteins has not been well defined except in IC.
Cellular Mechanisms of H+ Secretion and HCO3- Reabsorption
Primary H+ secretion as the mechanism of acid secretion in the distal nephron has been demonstrated by studies showing an acid luminal disequilibrium pH in the superficial distal tubule, in the cortical and outer medullary collecting tubules, and in papillary collecting tubules.        An apical membrane H+-ATPase is thought to be responsible for most of the H+ secretion along the collecting duct,   but H-K-ATPase discussed below likely contributes, particularly in certain conditions (see later discussion). This H+ ATPase is a member of the “vacuolar-type” H+ translocating ATPase that acidifies many intracellular organelles such as lysosomes, clathrin-coated vesicles, endosomes, Golgi-derived vesicles, endoplasmic reticulum, and chromaffin granules.    The H-ATPase is related by sequence and structure to the F1F0 H-ATPases, which includes mitochondrial ATP synthetase.   The vacuolar H-ATPases contain 8-10 subunits with a total molecular weight of 500 kD to 700 kD. This class of H-ATPases is inhibited by NEM, 7-chloro-4-nitrobenz-2-oxa-1, 3-diazole (NBD-Cl), DCCD, omeprazole, and bafilomycin, but resistant to vanadate, azide, and oligomycin.  
The initial evidence for H-ATPase mediating urine acidification derived from turtle bladder experiments.    The evidence that H-ATPase mediates urine acidification is considerable. First, the physiology of distal tubule H+ secretion correlates well with an electrogenic, sodium-independent ATP-requiring process.    Second, antibodies against H-ATPase stain the apical plasma membranes of ICs.    Third, OMCDis have H+secretion that is sensitive to luminal NEM. Also purified H-ATPase forms arrays of stud-like structures in liposomes that are identical to structures found in apical membranes of H+ secreting cells. And, finally as described in other chapters, mutations in subunits of H-ATPase cause distal renal tubular acidosis.  
Regulation of H+ ATPase occurs predominantly via recycling between the apical membrane and subapical vesicles, reviewed in Ref. 98. Insertion occurs in response to intracellular acidification or increased pCO2; these cause an increase in cell calcium that may be crucial.     This process is also microtubule/microfilament dependent and similar to mechanisms of neurosecretory exocytosis, involving SNARE and SNAP proteins.  
H+ATPase is electrogenic and therefore influenced by the effects of electrogenic Na+ reabsorption in Na+ transporting segments. (Parallel anion channels are present to shunt current in intracellular organelles, but not in most distal nephron H+ secreting cells; the superficial distal tubule may be an exception.)
An additional mechanism of regulation may be regulated assembly and disassembly of the H-ATPase subunits.   Also, cytosolic regulatory proteins of H+-ATPase have been identified, although the role remains uncertain.  An intriguing possible aspect of regulation is interaction with several glycolytic enzymes.   Transcriptional and translational regulation appears to be a less important mechanism of regulation, although the 31 kD subunit increases in IC with acidosis.   NEM sensitive ATPase increases with acidosis, but the mechanism is not clarified.  
Basolateral H+-ATPase likely mediates HCO3- secretion from type B IC; see later discussion. The distal tubule H+-ATPase shares most subunits with the proximal tubule H+-ATPase, except that the 56 kD subunit in the distal nephron is the B1 or “kidney isoform” and that in the proximal tubule is a distinct B2 subunit or “brain isoform”. Other subunits also differ.
H-K-ATPases also probably have a significant role in distal nephron acid secretion, especially with potassium deficiency.     These were first identified as K-ATPase activity in distal tubules that is insensitive to sodium and ouabain, but sensitive to inhibitors of the gastric H,K-ATPase.   Importantly, functional evidence for a role in H+ secretion was then found in perfused rabbit collecting ducts.   Functionally, H+ secretion by H,K-ATPase has usually been identified by inhibition with K+ removal or by the use of inhibitors such as omeprazole or SCH28080 (Schering-Plough, Kenilworth, NJ).
H-K-ATPases exchange H+ and K+ in an electroneutral manner. At least two isoforms of H-K-ATPase, gastric and colonic, are in the kidney; and strong evidence supports at least one additional type of H-K-ATPase in the distal nephron. These pumps are K-dependent ATPases of the E1,E2 class (P-type ATPase) Each have a unique a subunit (a1 for gastric and α2 for the colonic isoform) and a b subunit (a unique isoform for the gastric or the b subunit of Na-K-ATPase for the colonic pump).       The human ortholog of the α2 gene is probably ATP1AL1, also known as α4.   The colonic α2 subunit has at least two molecular variants.   The gastric isoform is sensitive to omeprazole and SCH28080, but not to ouabain; and the colonic isoform is sensitive to ouabain, but not SCH28080. Another isoform α3 has been found in toad bladder but not in mammals. At least three distinct types of H-K-ATPases have been determined in studies of the enzyme activities, but the correlation with transport studies is not totally clarified. The identity of a third isoform in mammals (in addition to gastric and colonic) has not been established. The isoforms of H-K-ATPase, which mediate acid-base and potassium transport in the collecting duct during various conditions has remained uncertain. Heterologous expression studies in Xenopus oocytes do not correspond well with functional studies in perfused kidney tubules. For instance, colonic H-K-ATPase expressed in oocytes is sensitive to ouabain, but not to SCH28080; however, in the distal tubule, studies have identified acid secre-tion sensitive to SCH28080, simultaneous with up-regulation of colonic H-K-ATPase, and down-regulation of gastric H-K-ATPase. Studies are on-going to identify additional isoforms, particularly ones up-regulated with potassium deficiency.   
Although animals with knockouts for either gastric or colonic H+-K+-ATPase have normal acid-base status,   compensatory adaptations may occur. New evidence for a novel form of H-K-ATPase comes from mice with no gastric isoform; CCD from these animals during potassium depletion have a ouabain and SCH28080 insensitive, K+ dependent H+ secretion.
Potassium deficiency stimulates omeprazole and SCH28080 sensitive HCO3- absorption and colonic H-K-ATPase mRNA, particularly in the medullary collecting duct.          Gastric H-K-ATPase may be stimulated in the CCD with potassium depletion.
Metabolic acidosis also stimulates H-K-ATPase activity.   In the OMCDis, 35% to 70% of HCO3- reabsorption is via H-K-ATPase under normal conditions,   but increased HCO3- reabsorption in response to metabolic acidosis is from increased H-ATPase.    The acute response to respiratory acidosis may be H,K-ATPase, at least in the CCD. The role of H-K-ATPase in bicarbonate secretion is not clear; although there is functional and mRNA expression data suggesting a role,   H-K-ATPase in the type B IC is at the apical membrane.    A role in sodium transport has been proposed because sodium can substitute for potassium to accomplish sodium absorption and low Na diets up-regulate H-K-ATPase activity.    NH4+ may also substitute for H+ and then H-K-ATPase secrete NH4+.   
The cellular distribution of H-K-ATPase in the distal nephron is complex, with differences found with various species, with technique (e.g., immunocytochemistry versus in situ hybridization studies), and even with different antibodies.     Both colonic and gastric isoforms are clearly located in ICs, but may also be present in certain principal cells (connecting segment cells) and even in some aspects of the TAL and macula densa.    As mentioned earlier, colonic type H-K-ATPase and H-K-ATPase activity has been found on the apical membrane of type B IC; the function there is uncertain.    
Basolateral Chloride-Bicarbonate Exchange
The basolateral HCO3- transport step in the H+ secreting cells of the distal nephron is Cl-/HCO3- exchange. Inhibition of basolateral Cl-/HCO3- exchange inhibits acid secretion and HCO3- reabsorption in the collecting duct.    Studies of pHi in IC of rabbit are also consistent with basolateral Na-independent Cl-/HCO3- exchange.     Conductive pathways or significant sodium-coupled pathways for HCO3- transport are not present in most distal tubule H+ secreting cells.    In the rat IMCDi, a basolateral HCO3- conductance has been found, without a basolateral Cl- channel.
This Cl-/HCO3- exchanger is a kidney form of AE1, also known as band 3 protein, the red blood cell exchanger involved in CO2 transport. Although a single gene encodes both the red cell and the kidney AE1, an alternate start site leads to an mRNA in the kidney, which has exons 1 through 3 deleted.    Therefore, the kidney AE 1 protein has a truncated N-terminus. The truncated part of the cytoplasmic domain is not directly involved in Cl-/HCO3- exchange.   Antibodies to AE1 stain the basolateral membranes of H+ secreting mitochondria rich cells of the turtle bladder and type A ICs of rat, rabbit, and human collecting ducts.     
AE1 (both renal and red blood cell forms) exchanges one chloride for one bicarbonate ion in an electroneutral fash-ion. The interstitium-to-cell chloride concentration gradient will therefore drive HCO3- extrusion from the cell. The driving force for basolateral Cl-/HCO3- exchange is the interstitium-to-cell Cl- concentration gradient because most studies of pHi in the collecting tubule suggest that the intracellular HCO3- is close to or below plasma HCO3-.    Cell Cl- will be low due to basolateral Cl- channels and the cell negative voltage. The basolateral membranes of H+ secreting cells are predominantly Cl- conductive.      At least one study has reported that the Km for Cl- in the OMCDis is in a range such that physiologic changes in extracellular [Cl-] could alter H+ secretion. In contrast, another study suggests that the exchanger is always saturated with Cl-.Basolateral AE1 in the collecting duct does adapt to acid-base conditions.  
AE2 is also on the basolateral membrane of collecting duct cells, particularly in the inner medulla.     AE4 discussed later may also mediate some of basolateral HCO3- extrusion. SLC26A7 may also be another mechanism of basolateral Cl-/HCO3- exchange in the OMCD.  
Cellular Mechanisms of HCO3- Secretion
Apical Chloride-Bicarbonate Exchange
HCO3- secretion from the type B IC occurs via an electroneutral, DIDS insensitive Cl-/HCO3- exchange process now thought to be pendrin (discussed later). The transport properties were demonstrated by transepithelial flux studies and directly demonstrated by studies of pHi in rabbit ICs.         The exchanger also mediates Cl- self-exchange (at a rate greater than Cl-/HCO3- exchange) and is activated by cAMP.       The relative DIDS resistance in vivo is an unusual feature of HCO3- transporters that is not shared by many transporters in heterologous expression systems. The apical Cl-/HCO3- exchanger in type B ICs is not likely the same protein as the basolateral Cl-HCO3- exchanger in type A IC. In addition to functional differences, the apical membranes of type B IC do not stain with antibodies to AE1, in contrast to the basolateral membranes of type A IC.     However, some investigators have suggested that AE1 could be responsible, just exhibiting different properties in the type B IC.     
Pendrin (SLC26A4), the gene product previously cloned as responsible for Pendred Syndrome, an autosomal recessive deafness and goiter, localizes to the apical membrane of HCO3- secreting type B IC and non-A, non-B IC. (Pendrin was originally identified as an iodine transporter.) CCD from mice deficit in pendrin do not secrete HCO3-.    Pendrin expression and distribution appears to be regulated as expected for a HCO3- secretory process, increasing with alkali loads and mineralocorticoids and decreasing with acid loads.      Pendrin expression appears to respond particularly to chloride balance and may participate in blood pressure regulation.    
A novel anion exchanger AE4 has been proposed to account for apical Cl-/HCO3- exchange, at least in the rabbit. However, recent studies have shown characteristics of AE4 that do not seem compatible with a general role in CCD HCO3- secretion: DIDS sensitive, basolateral membrane distribution in type A IC in rats, and lack of change with acid-base perturbations. In rabbits, AE4 is present on the apical membranes of type B IC.
Although an electroneutral apical Cl-/HCO3- exchanger clearly mediates mammalian HCO3- secretion, the situation is more complex in the turtle bladder, involving both electroneutral Cl-/HCO3- exchange and a separate electrogenic component during stimulation with alkaline loads, cAMP, or vasoactive intestinal peptide.     This process has not been demonstrated in mammalian distal tubules.
Basolateral H+ Extrusion
HCO3- secretion in the CCD is active and acetazolamide sensitive. The active driving force for HCO3- secretion is basolateral H extrusion and most evidence supports predominantly H-ATPase. Again, key findings were first identified in turtle bladder.   HCO3- secretion is insensitive to ouabain, peritubular amiloride, and removal of sodium.    (One study did show a decrease in HCO3- secretion with removal of sodium.) In the rat, H-ATPase antibodies stain the basolateral membrane of a portion of the IC in the CCD.     In rabbit CCD however, diffuse cytoplasmic staining, rather than basolateral staining, for H-ATPase, is seen in most lectin positive cells (type B ICs). However, H-ATPase is clearly seen in the basolateral membrane of some IC. Rod-shaped particles associated with H-ATPase are present in both membranes of rabbit CCD ICs and in the basolateral membrane of some rat ICs.   Although Na-H exchange is present on the basolateral membranes of type B ICs, no evidence supports a role in HCO3- secretion. There also appears to be a basolateral Na dependent Cl-/HCO3- exchange mechanism in type B IC. The possible role of H-K-ATPase is discussed earlier.
Basolateral Cl- channels are present in both type A and type B ICs. In type A IC, Cl- channels presumably recycle Cl- across the basolateral membrane, extruding Cl-, which enters the cells on the basolateral Cl-/HCO3- exchanger. A predominant basolateral Cl- conductance has been clearly demonstrated by electrophysiologic techniques in some H+ secreting cell types.    The apical membranes of H+ secreting cells from intact tubules do not appear to possess functional Cl- channels, despite the usual association of vacuolar H-ATPase with Cl- channels.    In contrast some cultured collecting duct cells do have apical Cl- channels. The chloride channel ClC-5 has been found to colocalize with H-ATPase in type A ICs, but its function there is unknown. ClC-5, which also is located in the proximal tubule, may function in endocytosis rather than in transepithelial transport.
Cl- channels are also present in the basolateral membranes of type B ICs. cAMP appears to activate basolateral Cl- channels in type B ICs in conjunction with acceleration of apical Cl-/HCO3- exchange.   Also, low concentrations of intracellular HCO3- activate these channels.    Recently, the chloride channel ClC-3 has been localized to type B ICs.
A basolateral Na-H exchanger (NHE-1) is present in most cells of the distal nephron.   This basolateral NHE-1 probably regulates intracellular pH and volume, but not transepithelial acid-base transport.
Electroneutral NBC-3 (or NBCn1) is present in the apical membrane of type A IC and OMCD cells, and in the basolateral membranes of type B IC and IMCD cells.    Little, if any, function in transepithelial acid-base transport is known.  
Cystic fibrosis transmembrane conductance regulator (CFTR) is also located in the collecting duct and could regulate other transporters, but its function in the collecting duct is unknown.
Regulation of Distal Nephron Acid-Base Transport
Acid-Base Balance and pH
The distal nephron usually responds appropriately to systemic acid-base changes (e.g., increasing HCO3- reabsorption and H+ secretion with acidosis). However, a number of factors also regulate distal nephron acid-base transport.
Acute or chronic acidosis stimulate distal nephron acid-base transport in several distal segments (reviewed extensively in Refs. 4, 386, 397, 589). In vivo, systemic acid-base changes alter U-B pCO2 (an index of distal nephron H secretion,    HCO3- transport in the superficial distal tubule,    and inner medullary H+ secretion. In vitro, acutely lowering basolateral pH by either lowering peritubular HCO3- or raising pCO2increases collecting duct luminal acidification and bicarbonate reabsorption.    Acute reductions in peritubular HCO3- will stimulate basolateral Cl-/HCO3- exchange, and the reduction in intracellular pH will stimulate insertion of H+ ATPase into the apical membrane from subapical vesicles.   As discussed earlier, this insertion process is calcium and microtubule/microfilament dependent, similar to mechanisms of neurosecretory exocytosis.    A similar process may occur for basolateral AE1. Some, but not all, studies demonstrate that increased peritubular pCO2 increases HCO3- reabsorption in the OMCDos and OMCDis.  
Acute changes in peritubular Cl- will also alter HCO3- transport due to effects on the basolateral Cl-/HCO3- exchanger in type A IC; peritubular Cl- will also alter transport in type B IC.    With low luminal Cl-, the HCO3- secretory process will be inhibited. This may be relevant to the maintenance and recovery from metabolic alkalosis.
Luminal pH also acutely alters H+ secretion. Decreasing luminal pH will inhibit the H-ATPase due to increased lumen to cell H+ gradient. However, luminal pH has minimal effects on cell pH or passive fluxes of HCO3- or H+, because the distal nephron has low apical membrane and paracellular permeabilities.      However, luminal HCO3- and pH do influence the pH of type B ICs based on the apical Cl-/HCO3- exchanger.
Chronic changes in acid-base balance in vivo induce more persistent adaptations in the distal nephron. With acid loading in vivo, HCO3- secretion decreases and the type B IC undergo morphologic and functional changes.        Similar persistent changes in transport are seen in superficial distal tubules and IMCD.    Some of these effects can occur rapidly with in vivo treatment. In segments such as the distal tubule and the CCD that can reabsorb or secrete HCO3-, changes in HCO3- secretion appear to be predominant over changes in HCO3- reabsorption,    although some data in the rat CCD show significant changes in both processes.
In the CCD, interconversion between type B and type A intercalated cells has been proposed as a major mechanism of adaptation.   In further studies, Schwartz, Al-Awqati, and colleagues have demonstrated possible reversal of po-larity of Cl-/HCO3- exchange. Although this was initially shown only in cultured cells,    more recent studies in freshly isolated CCD demonstrate similar findings. With acid media incubation, some type B IC not only lost apical Cl-/HCO3- exchange, but acquired basolateral Cl-/HCO3- exchange, an effect mediated in part by the extracellular protein hensin.      In fact, recent studies suggest that cyclosporine may cause distal renal tubular acidosis by intefering with hensin's function. However, total interconversion of cell type remains controversial. Immunocytochemical studies do show changes in the distributions of intercalated cells with particular patterns of staining for H+-ATPase with acid or alkali loads. Respiratory acidosis induces distinct changes in type A cells but no clear evidence of interconversion of cell types. The presence of numerous “atypical” cells in the CCD, discussed earlier, which are neither classic type A IC or classic type B IC, raises the issue of whether there are “hybrid cells,” which can modulate transport phenotype within some spectrum.
Regulation of H+-ATPase at the mRNA level is not thought to be a major mechanism of the response to acidosis, but there is some evidence of increases in at least the 31 kD subunit of H+-ATPase in acidosis. With acidosis, AE1 mRNA and protein increase.   Regulation of pendrin expression and localization may mediate changes in HCO3- secretion.  
The “signal” for these adaptive changes might not be pH per se because systemic pH is not necessarily changed; endothelin discussed later has been proposed to be such a signal. Renal cortical acid content may be altered even when systemic pH is normal. Acid loads in the form of protein induce distal tubule transport adaptations without major changes in systemic pH.   
Sodium delivery, Transepithelial Voltage, Angiotensin, and Mineralocorticoids
Classic studies demonstrated that sodium delivery and the accompanying anion have marked influences on distal nephron acidification.    Increasing sodium delivery, especially with non-reabsorbable anions, increases H+ secretion, particularly with volume depletion or increased mineralocorticoids. Because almost all of the mechanisms of H+ secretion in the distal nephron are Na+ independent, an indirect mechanism must be invoked: electrogenic H+ secretion responding to transepithelial voltage.   Increasing sodium delivery, poorly reabsorbable anions (anions other than chloride), and mineralocorticoids will increase the lumen negative transepithelial voltage and secondarily H+ secretion. This electrogenic response has been shown directly in CCD and OMCDis.    Chloride concentration gradients may also alter H+ secretion by altering transepithelial voltage.  
Changes in luminal Cl- and peritubular Cl- will alter HCO3- reabsorption and secretion by effects on the apical and basolateral Cl-/HCO3- transporters; low luminal Cl- will limit HCO3- secretion in the collecting duct.    Cl- delivery in vivo will be important because the Km for luminal Cl-/HCO3- exchange in B IC is approximately 5 μM to 10 μM. Luminal flow rate and HCO3- delivery also influence HCO3- transport in the rat superficial distal tubule.   
Mineralocorticoids are important determinants of net acid excretion.   In addition to the indirect voltage effects described earlier, mineralocorticoids directly stimulate H+ATPase.   This effect is directly seen in the OMCDis, which has no sodium reabsorption. A rapid nongenomic stimulation of H+ATPase has recently been reported in OMCD. Mineralocorticoids also stimulate IMCD H+ secretion. In contrast to the effects on H+ secretion, mineralocorticoids also stimulate bicarbonate secretion by type B IC, an effect that may be secondary to metabolic alkalosis.   
Angiotensin II has been reported to have a variety of direct effects on distal nephron acid-base transport. Angiotensin II increases HCO3- reabsorption in the superficial distal tubule.   However, it increases HCO3-secretion in the CCD and decreases HCO3- reabsorption in the OMCD.  
Hypokalemia or potassium depletion increases HCO3- reabsorption in the superficial distal tubule.   Similar findings have been made in the collecting duct. These findings parallel the increased ammonium production and enhanced proximal tubule HCO3- reabsorption with potassium depletion. Increased membrane insertion of H-ATPase in K depletion is a possible mechanism of the distal effects because an increased number of rod-shaped particles is found in ICs.
However, stimulation of distal nephron H-K-ATPase activity is likely very important as discussed previously.     Increased H-K-ATPase will cause both increased potassium reabsorption and increased H+ secretion. As reviewed, the mRNA of the colonic isoform of H-K-ATPase increases with potassium depletion, but the functional activity is sensitive to SCH28080, which should not affect the colonic isoform.     Another, so far unidentified, H-K-ATPase isoform may be induced by hypokalemia.   Alternatively, the properties of existing isoforms may be altered in potassium depletion.
Endothelin may be particularly important in the distal nephron, just as in the proximal tubule. Endothelin-1 levels in the renal interstitium increase with acidosis and stimulate superficial distal tubule H+ secretion via the ETBreceptor.   Endothelin-1 is released from microvascular endothelia cells. The increased HCO3- reabsorption may be due to increased Na-H exchange and decreased HCO3- secretion.   Recent in vitro studies indicate that the ETB receptor regulates the adaptation of the cortical collecting duct to metabolic acidosis, and that the NO-guanylate cyclase component of ETB receptor signaling mediates down-regulation of HCO3- secretion.
A variety of other hormones also modulate distal nephron acid-base transport, but the physiologic significance is not as certain. PTH stimulates distal nephron acidification,     and PTH increases with acidosis. A significant part of the effect of PTH may be from increased distal delivery of phosphate. Vasopressin also increases distal nephron acidification.    In contrast, angiotensin II increases CCD HCO3- secretion but increases HCO3- reabsorption in rat distal tubule. Prostaglandin E2 inhibits and indomethacin stimulates HCO3- reabsorption in the OMCDis to some extent. Prostacyclin (PGI2) increases rat distal tubule HCO3- secretion and alkali loads increase urinary metabolites of PGI2. Isoproterenol increases HCO3- secretion in the CCD via a cAMP-dependent mechanism. In contrast, HCO3- reabsorption increase in response to isoproterenol in the rat distal tubule and cAMP in the rabbit OMCDis. Glucagon stimulates HCO3- secretion in the rat superficial distal tubule in vivo.
Urinary excretion of ammonium (NH4+) accounts for approximately two thirds of net acid excretion usually, but can represent an even larger proportion of net acid excretion with acid loads. Production of NH4+ occurs predominantly from the metabolism of glutamine in the proximal tubule. NH4+ is a weak acid with a pKa of approximately 9.0:
NH4+ ➙ NH3 + H+
At physiologic pH, most of total ammonia (NH4+ and NH3) is in the form of NH4+. Based on this pKa, at pH 7 the ratio of NH4+ to NH3 is approximately 100:1. Therefore in contrast to historical concepts, physiologically NH3 is not an effective buffer because most is already protonated as NH4+. The manner in which NH4+ excretion in the urine represents acid excretion depends on the metabolism of glutamine. Complete deamidation of glutamine yields two NH4+ ions, and complete metabolism of the carbon skeleton of glutamine yields two HCO3-. (The carbon skeleton can alternatively be converted to glucose, as indicated in Figure 7-14 , which is ultimately metabolized elsewhere to HCO3-.) Therefore, glutamine metabolism produces both NH4+, which is excreted into the urine and HCO3-, which is returned to the blood. Because the excretion of NH4+ is linked quantitatively to the production of HCO3- conceptually (just as urinary H+ excretion as titratable acid is linked to production of HCO3-), excretion of NH4+ represents acid excretion. NH4+ that is not excreted in the urine will be metabolized in the liver to produce urea, a process consuming HCO3-, with no overall effect on acid-base balance. Therefore, only the NH4+ excreted into the urine is linked to the production of HCO3- and is the equivalent of acid excretion.
FIGURE 7-14 Major pathway of ammoniagenesis in the proximal tubule (with a cartoon of one large mitochondria). Gln, glutamine; glu, glutamate; aKG, alpha-ketoglutarate; GA, glutaminase I; GDH, glutamate dehydrogenase; PEPCK, phosphoenolpyruvate carboxykinase; PEP, phosphoenolpyruvate; TCA, tricarboxylic acid cycle enzymes; OAA, oxaloacetate. (Adapted from Curthoys NP, Gstraunthaler G: Mechanism of increased renal gene expression during metabolic acidosis. Am J Physiol Renal Physiol 281:F381–F390, 2001.)
NH4+ production results predominantly from the metabolism of glutamine (see Fig. 7-14 ).    Although all nephron segments appear to be capable of producing NH4+, the proximal tubule is quantitatively the most important and also the segment where there is adaptation to acidosis, in terms of both NH4+ production and key ammoniagenesis enzymes.     Many of the steps of NH4+ production and secretion into the urine are regulated by acid-base and potassium balance, as discussed later.
Ammoniagenesis and the response to acidosis have been extensively reviewed,    and will only be briefly described (see Fig. 7-14 ). Ammoniagenesis is increased by both acute and chronic acidosis. Several enzymes involved in ammoniagenesis appear to be most important in this regulation: glutaminase I, glutamate dehydrogenase, and PEPCK. However, multiple steps are involved. Release of glutamine from muscles and glutamine uptake into proximal tubule cells from both the luminal fluid and from the basolateral aspect of the cells is stimulated by acidosis.   Uptake of glutamine from the cytoplasm into mitochondria then occurs via a specific transporter that is stimulated by acidosis. Mitochondrial glutaminase I (also called phosphate-dependent glutaminase) then initiates the most important pathway of ammoniagenesis. Glutaminase is present in other nephron segments, but in these locations is not regulated by acid-base balance nor is quantitatively as significant. Glutaminase I deamidates glutamine to yield glutamate and one NH4+. When ammoniagenesis is stimulated, an additional NH4+ results from the oxidative deamination of glutamate (also yielding alpha ketoglutarate) by glutamate dehydrogenase (GDH) in the mitochodria. Glutaminase I and GDH are both up-regulated by acid loads, predominantly by an increase in mRNA stability of these enzymes.     With glutaminase, the increase in mRNA stability may result from a pH responsive binding of zeta-crystallin/NADPH:quinone reductase to an eight-base AU sequence in the 3′-untranslated region of the mRNA. Metabolism of alpha-ketoglutarate by alpha-ketoglutarate dehydrogenase and Krebs cycle enzymes results in malate, which is then transported from the mitochondria to the cytoplasm. Alpha-ketoglutarate dehydrogenase is also stimulated by acidosis. Malate is converted to oxaloacetate and finally to phosphoenolpyruvate by phosphoenolpyruvate carboxykinase (PEPCK). PEPCK, in addition to glutaminase and GDH, is also importantly regulated by acid-base homeostasis. PEPCK is induced by mRNA transcription. Increased transcription of PEPCK occurs via an acidosis induced phosphorylation of p38 MAPK and activating transcription factor-2 (ATF-2) acting via the cAMP-response element-1 site of the PEPCK promoter. The phosphoenolpyruvate can be metabolized to either produce glucose or further metabolized to yield HCO3-. NH4+ can be produced by other metabolic pathways (such as gamma-glutamyltranspeptidase) but these are thought to be less important.
Chronic hypokalemia, probably via an intracellular acidosis, also stimulates ammoniagenesis.    In contrast, hyperkalemia reduces both ammoniagenesis and NH4+ transport in the TAL and consequent transfer into the collecting duct.    
Angiotensin II increases ammoniagenesis and transport of ammonia from the proximal tubule cell into the lumen.   Other hormones such as insulin, PTH, dopamine, and alpha adrenergic agonists also increase ammoniagenesis.   As discussed earlier, glucocorticoids increase with acidosis, and in turn glucocorticoids also stimulate ammoniagenesis.    Prostaglandins inhibit ammoniagenesis.
NH4+ and NH3 Transport
Total ammonia transport has often been considered to occur by free lipophilic diffusion of NH3 across all cell membranes and trapping of NH4+ in the acidic tubular lumen. This simple concept has gradually been replaced over the past several years with information that NH4+ transport occurs on a variety of membrane transporters and that NH3 diffusion does not occur across all tubule segments with equally high permeability.     Although permeabilities to NH3 are high, particularly in the proximal tubule, NH3 concentrations are not in equilibrium,      as expected for CO2.
As discussed earlier, total ammonia is produced predominantly in the proximal tubule and NH4+ produced there is preferentially secreted into the tubule lumen. However, a substantial portion of NH4+ produced in the kidneys exits via the renal veins, instead of being excreted into the urine. Secretion of ammonia in the proximal tubule occurs by both NH3 diffusion and by NH4+ transport on the apical Na-H exchanger.   NH4+ transport on the Na-H exchanger was first demonstrated in membrane vesicles, but later also demonstrated to occur in intact mouse proximal tubules in vitro.   However, studies using rat proximal tubules in vivo demonstrated that total ammonia transport probably occurs nearly equally by NH3 diffusion and NH4+ movement on the Na-H exchanger.    (Experimentally, NH4+ transport is difficult to separate from parallel NH3 and H+ transport.) NH3 diffusion is facilitated by a low luminal pH created by H+ secretion; this keeps the luminal NH3 concentration low. And NH4+ secretion will be accelerated by stimuli that increase Na-H exchanger activity. Therefore, both NH3 transport and NH4+ transport on the Na-H exchanger will be accelerated by increased activity of the Na-H exchanger. NH4+ transport in the proximal tubule may also occur via a barium-sensitive K+ pathway. NH4+ may substitute for K+on the basolateral Na-K-ATPase   and there may also be a basolateral K+/NH4+ exchanger. Angiotensin II and increasing luminal flow rate stimulate NH4+ production and secretion into the proximal tubule lumen.   In normal conditions, total ammonia is secreted by the early proximal tubule and is reabsorbed to some extent late in the proximal tubule; with chronic acidosis, ammonia secretion also occurs in the late proximal tubule, stimulated by angiotensin II.   More than 20% of ammonia produced in the proximal tubule is released across the basolateral membrane and reaches the renal venous blood.  
Although NH4+ is produced and secreted in the proximal tubule, much of the NH4+ does not simply traverse down the tubule lumen. Total ammonia delivered to the loop of Henle is higher than that at the end of the superficial proximal tubule, but is considerably less at the beginning of the superficial distal tubule. Therefore, total ammonia is lost or reabsorbed in the ascending loop of Henle and/or thick ascending limb.     Ammonia may be secreted into the descending limb of Henle (and perhaps late proximal straight tubule) but is then reabsorbed in the thick ascending limb. The total ammonia lost in the loop of Henle, however, is eventually secreted into the collecting duct for excretion into the urine. The reabsorption and concentration of total ammonia by the loop of Henle and thick ascending limb indicates recycling and countercurrent concentration for total ammonia, creating high concentrations in the deep medulla. Total ammonia concentrations in the renal interstitium increase from the outer medullary region to higher concentrations in the deep papilla as illustrated in Figure 7-15 . This creates a concentration driving force for secretion into the late collecting duct. NH3 concentrations in the loop of Henle will be increased by the high luminal pH values (see earlier discussion of medullary concentration of HCO3- in the loop as water is extracted); and NH3 concentrations in the collecting duct will be decreased by H+ secretion.
FIGURE 7-15 Overall scheme of ammonia transport along the nephron. Numbers (%) refer to percentage of delivery to each site compared to final urine; data from 2, 163, 665, 666, 678, 679. These numbers are shown to illustrate the large addition of ammonia in the proximal tubule, the high concentrations in the loop of Henle, and the loss of ammonia before the distal tubule. (Adapted from Hamm LL, Alpern RJ: Cellular mechanisms of renal tubular acidification. In Seldin DW, Giebisch G (eds): The Kidney: Physiology and Pathophysiology. Philadelphia, Lippincott Williams & Wilkins, 2000, pp 1935-1979.)
NH4+ reabsorption in the thick ascending limb is the driving force for medullary concentration of total ammonia. NH4+ is absorbed despite the simultaneous reabsorption of HCO3-; therefore NH4+ transport in the TAL occurs in a direction opposite to that expected for non-ionic diffusion of NH3 and “trapping” of NH4+. In fact, non-ionic diffusion of NH3 is limited in the TAL because of an apical membrane that has a low permeability to NH3.  (Initially the low NH3 permeability, relative to NH4+ entry in TAL, was interpreted as an impermeable apical membrane; later analysis has suggested that the NH3 permeability is only relatively low compared to NH4+ entry, probably due to a small surface area compared to the basolateral membrane.   )
NH4+ is transported from the lumen of the thick ascending limb by several mechanisms: substitution for K+ on both the Na-K-2Cl transporter (also known as BSC1 or NKCC2) and the apical membrane K+ channel.   The Na-K-2Cl transporter in the TAL is enhanced in metabolic acidosis and by the increase in glucocorticoids that occurs with acidosis.   In addition, there is a separate NH4+ conductance (amiloride sensitive) and an electroneutral K+/NH4+ (or H+) exchanger (verapamil and barium sensitive).     NH4+ can also be transported on Na-H exchangers and Na-K-ATPase as discussed earlier. Also some NH4+ may be driven through the paracellular pathway by the lumen positive voltage; this has been estimated to account for some 35% of TAL NH4+ transport.   Consistent with the physiologic importance of the TAL for NH4+ transport, NH4+ transport in the TAL is increased by acidosis and decreased by increasing potassium concentration.    However, NH4+ and HCO3- reabsorption are also increased with metabolic alkalosis induced by NaHCO3 loading (a response inappropriate for correction of the alkalosis), probably secondary to the increased delivery of NaCl to this segment in vivo.
Ammonia secretion along the collecting duct is critical for urinary excretion. Total ammonia secretion in the collecting duct occurs in large part by non-ionic diffusion of NH3, driven by the concentration gradient for NH3, which is maintained by high medullary interstitial concentrations of NH3.     As discussed earlier, NH3 concentrations increase deeper in the medulla. This secretion is abetted by H+ secretion and an acid luminal disequilibrium pH in most segments of the collecting duct  ; without H+ secretion, collecting duct luminal pH and NH3 concentrations would rise concurrently as NH3 entered. Although non-ionic diffusion of NH3 has been presumed (with some experimental verification) to account for much of total ammonia transport in the collecting duct, recent evidence suggests that facilitated transport, perhaps via Rh proteins discussed later, may account for a significant portion of this transport across both apical and basolateral membranes.  
In the collecting duct, total ammonia may be transported across the basolateral membrane by NH4+ substitution for potassium on the Na-K-ATPase.    NH4+ may serve as a proton source for acid secretion. There is competition between K+ and NH4+, so that NH4+ uptake increases with lower interstitial K+ concentrations. NH4+ transport across the apical membrane may occur on H-K-ATPase, by substitution for potassium, particularly in states of potassium deficiency.    Recent studies have shown that NH3 can be transported by water channels (AQP1),   but the physiologic importance of this has not been established. Although, NH4+ can be transported on the Na-K-2Cl co-transporter (BSC2) in the inner medullary collecting duct and is up-regulated by acidosis, this transporter does not greatly alter acid-base transport.     An NH4+/K+ exchanger that is sensitive to verapamil and SCH28080 has also been described in cultured inner medullary collecting duct cells.
Recently, two new described membrane proteins belonging to the erythrocyte Rh family have been proposed to be involved in NH3 and/or NH4+ transport (for a review see Refs. 663, 705). In the kidney, RhCG and RhBG are respectively expressed in the apical and basolateral membranes of the intercalated cells of the distal nephron including the connecting tubule and the cortical and medullary collecting ducts.   However, localization in CCD principal cells is also found and RhCG is also found on the basolateral membranes depending on species.    Metabolic acidosis causes increased RhCG protein and redistribution within cells, whereas no changes in RhBG are found.   Several studies indicate that these membrane proteins act as carriers of NH4+ transport. RhCG and RhBG were reported to be electroneutral NH4+-H+ exchangers.   Other studies proposed that RhCG actually transports NH3 and possibly CO2. When expressed in oocytes, Rhbg was reported to be an electrogenic NH4+ transporter. Based on recently resolved crystallographic structure of bacterial Amt-B (a related protein), Rh glycoproteins were proposed to act as gas channels through a unique mechanism involving recruitment of NH4+ and passage of NH3 through a hydrophobic core. Increasingly, evidence is accumulating to indicate that renal NH4+-specific transporters may actually be the Rh glycoproteins. Of note however, animals with knock out of Rhbg do not have acid-base abnormalities or detectable defects in ammonia transport; whether this represents redundancy of transporters or other adaptation has not been determined.
In sum, NH4+ excretion into the urine is regulated by three processes: ammoniagenesis, specific transport of NH4+, and by H+ secretion.    Regulation of NH4+ transport occurs in the proximal tubule, in the TAL (and resulting medullary concentration of total ammonia), and in the collecting duct.
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