BACKGROUND: The electroneutral Na
+/HCO
3
- 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
4
+ transport measured in isolated perfused mTALs. Quantitative RT-PCR and immunoblotting were used to evaluate NBCn1 expression. Tissue [NH
4
+] was measured in renal biopsies, NH
4
+ excretion and titratable acid quantified in spot urine, and arterial blood gasses evaluated in normoventilated mice.
RESULTS: Basolateral Na
+/HCO
3
- cotransport activity was similar in isolated perfused mTALs from wild-type and NBCn1 knockout mice under control conditions. During metabolic acidosis, basolateral Na
+/HCO
3
- 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
4
+ reabsorption across mTALs by approximately 60%, abolished the renal corticomedullary NH
4
+ gradient, reduced the capacity for urinary NH
4
+ excretion by approximately 50%, and delayed recovery of arterial blood pH and standard [HCO
3
-] from their initial decline.
CONCLUSIONS: During metabolic acidosis, NBCn1 is required for the upregulated basolateral HCO
3
- uptake and transepithelial NH
4
+ reabsorption in mTALs, renal medullary NH
4
+ accumulation, urinary NH
4
+ excretion, and early recovery of arterial blood pH and standard [HCO
3
-]. These findings support that NBCn1 facilitates urinary net acid excretion by neutralizing intracellular H
+ released during NH
4
+ reabsorption across mTALs.