Of the various solutes reabsorbed in the proximal tubule, the most relevant to diuretic action are NaHCO3 and NaCl. Until recently, of the currently available diuretics, only one group (carbonic anhydrase inhibitors, which block NaHCO3 reabsorption) has acted predominantly in the PCT. Sodium bicarbonate reabsorption by the PCT is initiated by the action of a Na+/ exchanger (NHE3) located in the luminal membrane of the proximal tubule epithelial cell (Figure 15–2). This transport system allows Na+ to enter the cell from the tubular lumen in exchange for a proton (H+) from inside the cell. As in all portions of the nephron, Na+/K+-ATPase in the basolateral membrane pumps the reabsorbed Na+ into the interstitium in order to maintain a low intracellular Na+ concentration. The H+ secreted into the lumen combines with bicarbonate (HCO3−) to form H2CO3 (carbonic acid), which is rapidly dehydrated to CO2 and H2O by carbonic anhydrase. Carbon dioxide produced by dehydration of H2CO3 enters the proximal tubule cell by simple diffusion, where it is then rehydrated back to H2CO3, facilitated by intracellular carbonic anhydrase. After dissociation of H2CO3, the H+ is available for transport by the Na+/H+ exchanger, and the HCO3− is transported out of the cell by a basolateral membrane transporter (Figure 15–2). Bicarbonate reabsorption by the proximal tubule is thus dependent on carbonic anhydrase activity. This enzyme
TABLE 15–1 Major segments of the nephron and their functions.
Glomerulus Formation of glomerular filtrate Extremely high None
Proximal convoluted Reabsorption of 65% of filtered Na+/K+/ Very high Na/H1 (NHE3), carbonic tubule (PCT) CA2+, and Mg2+; 85% of NaHCO3, and nearly anhydrase; Na/glucose 100% of glucose and amino acids. Isosmotic cotransporter 2 (SGLT2) reabsorption of water.
Proximal tubule, straight Secretion and reabsorption of organic acids Very high Acid (eg, uric acid) and segments and bases, including uric acid and most
Carbonic anhydrase inhibi-tors, Adenosine antagonists (under investigation)
Thin descending limb Passive reabsorption of water High Aquaporins None of Henle’s loop
Thick ascending limb of Active reabsorption of 15–25% of filtered Very low Na/K/2Cl (NKCC2) Loop diuretics Henle’s loop (TAL) Na+/K+/Cl−; secondary reabsorption of CA2+
Distal convoluted tubule Active reabsorption of 4–8% of filtered Na+ Very low Na/Cl (NCC) Thiazides (DCT) and Cl−; CA2+ reabsorption under parathy-roid
Cortical collecting Na+ reabsorption (2–5%) coupled to K+ and Variable2 Na channels (ENaC), K+-sparing diuretics tubule (CCT) H+ secretion
K channels,1 H+ trans-Adenosine antagonists porter,1 aquaporins (under investigation) 1Not a target of currently available drugs. 2Controlled by vasopressin activity.