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Abstract
Background The electroneutral Na+/HCO3− 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 NH4+ transport measured in isolated perfused mTALs. Quantitative RT-PCR and immunoblotting were used to evaluate NBCn1 expression. Tissue [NH4+] was measured in renal biopsies, NH4+ excretion and titratable acid quantified in spot urine, and arterial blood gasses evaluated in normoventilated mice.
Results Basolateral Na+/HCO3− cotransport activity was similar in isolated perfused mTALs from wild-type and NBCn1 knockout mice under control conditions. During metabolic acidosis, basolateral Na+/HCO3− 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 NH4+ reabsorption across mTALs by approximately 60%, abolished the renal corticomedullary NH4+ gradient, reduced the capacity for urinary NH4+ excretion by approximately 50%, and delayed recovery of arterial blood pH and standard [HCO3−] from their initial decline.
Conclusions During metabolic acidosis, NBCn1 is required for the upregulated basolateral HCO3− uptake and transepithelial NH4+ reabsorption in mTALs, renal medullary NH4+ accumulation, urinary NH4+ excretion, and early recovery of arterial blood pH and standard [HCO3−]. These findings support that NBCn1 facilitates urinary net acid excretion by neutralizing intracellular H+ released during NH4+ reabsorption across mTALs.
- Copyright © 2021 by the American Society of Nephrology
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