NBCn1 Increases NH Reabsorption Across Thick Ascending Limbs, the Capacity for Urinary NH Excretion, and Early Recovery from Metabolic Acidosis.

Background: The electroneutral Na/HCO cotransporter NBCn1 (Slc4a7) is expressed in basolateral membranes of renal medullary thick ascending limbs (mTALs). However, direct evidence that NBCn1 contributes to acid-base handling in mTALs, urinary net acid excretion, and systemic acid-base homeostasis has been lacking.

Methods: Metabolic acidosis was induced in wild-type and NBCn1 knockout mice. Fluorescence-based intracellular pH recordings were performed and NH transport measured in isolated perfused mTALs. Quantitative RT-PCR and immunoblotting were used to evaluate NBCn1 expression. Tissue [NH ] was measured in renal biopsies, NH excretion and titratable acid quantified in spot urine, and arterial blood gasses evaluated in normoventilated mice.

Results: Basolateral Na/HCO cotransport activity was similar in isolated perfused mTALs from wild-type and NBCn1 knockout mice under control conditions. During metabolic acidosis, basolateral Na/HCO cotransport activity increased four-fold in mTALs from wild-type mice, but remained unchanged in mTALs from NBCn1 knockout mice. Correspondingly, NBCn1 protein expression in wild-type mice increased ten-fold in the inner stripe of renal outer medulla during metabolic acidosis. During systemic acid loading, knockout of NBCn1 inhibited the net NH reabsorption across mTALs by approximately 60%, abolished the renal corticomedullary NH gradient, reduced the capacity for urinary NH excretion by approximately 50%, and delayed recovery of arterial blood pH and standard [HCO ] from their initial decline.

Conclusions: During metabolic acidosis, NBCn1 is required for the upregulated basolateral HCO uptake and transepithelial NH reabsorption in mTALs, renal medullary NH accumulation, urinary NH excretion, and early recovery of arterial blood pH and standard [HCO ]. These findings support that NBCn1 facilitates urinary net acid excretion by neutralizing intracellular H released during NH reabsorption across mTALs.