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NBCn1 increases NH4+ reabsorption across thick ascending limbs, the capacity for urinary NH4+ excretion, and early recovery from metabolic acidosis

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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.

Original languageEnglish
JournalJournal of the American Society of Nephrology
Pages (from-to)852-865
Number of pages14
Publication statusPublished - Apr 2021

    Research areas

  • AMMONIUM, CELLS, COTRANSPORTER NBCN1, INTRACELLULAR PH, LOCALIZATION, NA+, PERFUSION, S0859, SLC4A7, TRANSPORT, acidosis, cell & transport physiology, intracellular pH, ion transport

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ID: 201314558