In a patient with proximal renal tubular acidosis (type 2 RTA), the primary defect is reduced bicarbonate reabsorption in the proximal tubule. The molecular mechanism most directly responsible involves dysfunction of which transporter?

• A H+-ATPase on the alpha-intercalated cells of the collecting duct
• B Cl-/HCO3- exchanger (pendrin) on the luminal membrane of type B intercalated cells
• C Carbonic anhydrase IV in the thick ascending limb of Henle
• D Na+/H+ exchanger (NHE3) on the luminal membrane coupled with basolateral Na+/HCO3- cotransporter (NBC1) ✓

Explanation

In the proximal tubule, HCO3- reabsorption depends on luminal Na+/H+ exchange (NHE3) which secretes H+; carbonic anhydrase IV converts luminal H2CO3 to CO2 that diffuses into the cell; intracellular carbonic anhydrase II reforms HCO3-, which exits via the basolateral NBC1 cotransporter. Dysfunction of NHE3, carbonic anhydrase II, or NBC1 causes type 2 RTA. The H+-ATPase defect is responsible for type 1 (distal) RTA; pendrin dysfunction causes type 4B RTA affecting bicarbonate secretion in the collecting duct.

Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.

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