NBCe1-a regulates proximal tubule ammonia metabolism under basal conditions and in response to metabolic acidosis

Hyun Wook Lee, Gunars Osis, Autumn N. Harris, Lijuan Fang, Michael F Romero, Mary E. Handlogten, Jill W. Verlander, I. David Weiner

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Renal ammonia metabolism is the primary mechanism through which the kidneys maintain acid-base homeostasis, but the molecular mechanisms regulating renal ammonia generation are unclear. In these studies, we evaluated the role of the proximal tubule basolateral plasma membrane electrogenic sodium bicarbonate cotransporter 1 variant A (NBCe1-A) in this process. Deletion of the NBCe1-A gene caused severe spontaneous metabolic acidosis in mice. Despite this metabolic acidosis, which normally causes a dramatic increase in ammonia excretion, absolute urinary ammonia concentration was unaltered. Additionally, NBCe1-A deletion almost completely blocked the ability to increase ammonia excretion after exogenous acid loading. Under basal conditions and during acid loading, urine pH was more acidic in mice with NBCe1-A deletion than in wild-type controls, indicating that the abnormal ammonia excretion was not caused by a primary failure of urine acidification. Instead, NBCe1-A deletion altered the expression levels of multiple enzymes involved in proximal tubule ammonia generation, including phosphate-dependent glutaminase, phosphoenolpyruvate carboxykinase, and glutamine synthetase, under basal conditions and after exogenous acid loading. Deletion of NBCe1-A did not impair expression of key proteins involved in collecting duct ammonia secretion. These studies demonstrate that the integral membrane protein NBCe1-A has a critical role in basal and acidosis-stimulated ammonia metabolism through the regulation of proximal tubule ammonia-metabolizing enzymes.

Original languageEnglish (US)
Pages (from-to)1182-1197
Number of pages16
JournalJournal of the American Society of Nephrology
Volume29
Issue number4
DOIs
StatePublished - Apr 1 2018

ASJC Scopus subject areas

  • Nephrology

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