Document Detail

NHE4 is critical for the renal handling of ammonia in rodents.
MedLine Citation:
PMID:  20484819     Owner:  NLM     Status:  MEDLINE    
Ammonia absorption by the medullary thick ascending limb of Henle's loop (MTALH) is thought to be a critical step in renal ammonia handling and excretion in urine, in which it is the main acid component. Basolateral Na+/H+ exchangers have been proposed to play a role in ammonia efflux out of MTALH cells, which express 2 exchanger isoforms: Na+/H+ exchanger 1 (NHE1) and NHE4. Here, we investigated the role of NHE4 in urinary acid excretion and found that NHE4-/- mice exhibited compensated hyperchloremic metabolic acidosis, together with inappropriate urinary net acid excretion. When challenged with a 7-day HCl load, NHE4-/- mice were unable to increase their urinary ammonium and net acid excretion and displayed reduced ammonium medulla content compared with wild-type littermates. Both pharmacologic inhibition and genetic disruption of NHE4 caused a marked decrease in ammonia absorption by the MTALH. Finally, dietary induction of metabolic acidosis increased NHE4 mRNA expression in mouse MTALH cells and enhanced renal NHE4 activity in rats, as measured by in vitro microperfusion of MTALH. We therefore conclude that ammonia absorption by the MTALH requires the presence of NHE4 and that lack of NHE4 reduces the ability of MTALH epithelial cells to create the cortico-papillary gradient of NH3/NH4+ needed to excrete an acid load, contributing to systemic metabolic acidosis.
Soline Bourgeois; Leonie Van Meer; Bharath Wootla; May Bloch-Faure; Régine Chambrey; Gary E Shull; Lara R Gawenis; Pascal Houillier
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-05-17
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  120     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2010 Jun 
Date Detail:
Created Date:  2010-06-02     Completed Date:  2010-06-21     Revised Date:  2012-02-07    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1895-904     Citation Subset:  AIM; IM    
INSERM, Centre de Recherche des Cordeliers, UMRS872, Paris, France.
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MeSH Terms
Acidosis / genetics,  metabolism*
Ammonia / metabolism,  urine
Biological Transport / genetics
Epithelial Cells / metabolism
Kidney / metabolism,  physiology*
Loop of Henle / metabolism*
Mice, Knockout
Quaternary Ammonium Compounds / metabolism*
Rats, Sprague-Dawley
Rodentia / genetics,  metabolism*
Specific Pathogen-Free Organisms
Reg. No./Substance:
0/Quaternary Ammonium Compounds; 7664-41-7/Ammonia

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