Mechanisms of bicarbonate reabsorption and bicarbonate generation

Panel A: The major proximal tubule cellular and luminal events that result in HCO₃^– reclamation are shown. Intracellular H₂O combines with CO₂ to generate H₂CO₃. The H₂CO₃ rapidly dissociates into H⁺ and HCO₃^– ions. The cytoplasmic enzyme carbonic anhydrase II catalyzes these reactions. Electrogenic Na⁺ K⁺ ATPase pumps in the basolateral (anti-luminal) membrane move Na⁺ out of the cell and K⁺ into the cell, generating a steep Na⁺ electrochemical gradient from the lumen into the cell. This energizes Na⁺ reabsorption via the NHE3. H⁺ that moves into the lumen reacts with filtered HCO₃^– forming H₂CO₃. The H₂CO₃ then dehydrates to become H₂O and CO₂. The dehydration reaction is catalyzed by intraluminal carbonic anhydrase IV. Intraluminal carbonic anhydrase IV is tethered to the luminal membrane. The CO₂ generated in the lumen flows into the cell, largely via the AQP1 channel. On the other side of the cell, HCO₃^– ions that have been generated move into the interstitial space and peritubular capillaries, primarily via NBCe1A (an electrogenic transporter and product of the solute carrier family 4 member 4 [SLC4A4] gene). In aggregate, the secretion of 1 H⁺ molecule is linked to the reabsorption of 1 Na⁺ molecule and results in the addition of 1 NaHCO₃ molecule to the extracellular fluid. Although the HCO₃^– ions that enter the extracellular fluid are not the actual filtered ions, the net effect is reclamation of filtered NaHCO₃ and its return to the circulation. Additionally, a smaller component of proximal tubule H⁺ secretion (which also results in HCO₃^– reclamation) is due to a V-type H⁺ ATPase pump complex. The proximal tubule is responsible for reclaiming approximately 90% of the filtered NaHCO₃.
Panel B: The major ion transporting cells in the distal tubules are principal cells and intercalated cells (there are 3 intercalated cell subtypes: type A, type B, and nontype A/nontype B). These cells are located in the late distal convoluted tubule, connecting tubule, and cortical collecting duct. The principal cells are primarily energized by electrogenic Na⁺ K⁺ ATPase pumps located in the basolateral membranes. Na⁺ K⁺ ATPase activity creates a low intracellular [Na⁺] and a negative intracellular potential difference. This large electrochemical Na⁺ gradient causes Na⁺ to move from the lumen into the cells, mainly through the ENaC. The inward flow of Na⁺ ions is more rapid than the sum of outward movement of K⁺ (mainly through the ROMK) and inward flow of Cl^– (mainly via the paracellular space). Therefore, the influx of Na⁺ cations generates a relative negative potential difference in the lumen, which stimulates the movement of K⁺ and H⁺ into the lumen. In type A intercalated cells, intracellular H₂O combines with CO₂ to generate H₂CO₃. The H₂CO₃ rapidly dissociates into H⁺ and HCO₃^– ions. The cytoplasmic enzyme carbonic anhydrase II catalyzes these reactions. The HCO₃^– ions move into the interstitial space and peritubular capillaries in exchange for Cl^– ions via AE1 (a product of the solute carrier family 4 member 1 [SLC4A1] gene). This process reclaims the 10% of filtered HCO₃^– not normally reclaimed in the proximal tubule. The H⁺ ions are pumped into the lumen mainly via an electrogenic V-type H⁺ ATPase pump complex and to a smaller degree by an H⁺ K⁺ ATPase pump. In the lumen, the H⁺ combines with NH₃ to form NH₄⁺ and also with HPO₄^–2 to form H₂PO₄^– (ie, titratable acid). The H⁺ K⁺ ATPase pump is also important for the conservation of K⁺.