HCO₃⁻ reclamation in the renal proximal tubule

Reclamation of HCO₃⁻ in the kidney has a key role in the regulation of systemic acid–base balance. Approximately 80% of HCO₃⁻ reclamation occurs in the proximal tubule and is thought to depend on the secretion of H⁺ into the tubule lumen via the apical Na⁺/H⁺ exchanger NHE3 and the vacuolar-type H⁺ pump. Now, Yi-Min Guo and colleagues report that HCO₃⁻ is also reclaimed via a direct pathway involving the electroneutral Na⁺/HCO₃⁻ cotransporter NBCn2.

Credit: Simon Bradbrook/Macmillan Publishers Limited

Previous studies in rat kidneys identified two full-length variants of NBCn2 that differ in their amino termini: MCDL-NBCn2 and MEIK-NBCn2. In their recent study, Guo et al. report that in the rat kidney, MEIK-NBCn2 is primarily expressed at the basolateral membranes of the medullary thick ascending limbs, whereas MCDL-NBCn2 is primarily expressed at the apical membranes of the proximal tubules. Based on this apical localization, they hypothesize that MCDL-NBCn2 mediates Na⁺/HCO3⁻ influx from the tubule lumen to the cytosol.

MCDL-NBCn2 mediates Na⁺/HCO₃⁻ influx from the tubule lumen to the cytosol

To investigate the physiological relevance of apical MCDL-NBCn2 expression, the researchers investigated the effects of systemic acid–base disturbances on the renal expression of MCDL-NBCn2 and NHE3 in rats. They found that 2 weeks of NH₄Cl-induced metabolic acidosis led to downregulation of MCDL-NBCn2 expression by ∼31% and upregulation of NHE3 expression by ∼97% compared with controls. Conversely, 2 weeks of metabolic alkalosis induced by NaHCO₃ overload led to a ∼52% increase in MCDL-NBCn2 expression and ∼46% decrease in NHE3 expression. Hypokalaemic alkalosis induced by potassium depletion for 2 weeks led to a decrease in MCDL-NBCn2 abundance by ∼45% and an increase in NHE3 expression by ∼121% compared with controls. These findings indicate an inverse relationship between the regulation of MCDL-NBCn2 and NHE3 expression.

“The [proximal tubule] reciprocally regulates MCDL-NBCn2 and NHE3 under conditions that require reciprocal modulation of HCO₃⁻ reclamation versus new HCO₃⁻ creation,” state Guo et al. “Indeed, our mathematical simulations show that these two pathways, appropriately, have reciprocal efficiencies for HCO₃⁻ reclamation versus creation of new HCO₃⁻. These predictions call for testing in future studies.”

The researchers conclude that their findings are consistent with the hypothesis that proximal tubule apical membranes reabsorb HCO₃⁻ by two strategies. “The major one is the classic indirect CO₂ pathway, depending on H⁺ secretion by the apical NHE3 and proton pumps. The minor one is the direct HCO₃⁻ pathway, in which NBCn2 transfers HCO₃⁻ across the apical membrane.”