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Intercalated Cell Depletion and Vacuolar H-ATPase Mistargeting in an Ae1 R607H Knockin Model.

Citation
Mumtaz, R., et al. “Intercalated Cell Depletion And Vacuolar H-Atpase Mistargeting In An Ae1 R607H Knockin Model.”. Journal Of The American Society Of Nephrology : Jasn, pp. 1507-1520.
Center Boston Area
Author Rizwan Mumtaz, Francesco Trepiccione, Christopher Hennings, Antje K Huebner, Bettina Serbin, Nicolas Picard, A K M Shahid Ullah, Teodor G Păunescu, Diane E Capen, Rawad M Lashhab, Isabelle Mouro-Chanteloup, Seth L Alper, Carsten A Wagner, Emmanuelle Cordat, Dennis Brown, Dominique Eladari, Christian A Hübner
Keywords Cell & Transport Physiology, chronic metabolic acidosis, distal tubule, genetic renal disease, ion transport, transgenic mouse
Abstract

Distal nephron acid secretion is mediated by highly specialized type A intercalated cells (A-ICs), which contain vacuolar H-ATPase (V-type ATPase)-rich vesicles that fuse with the apical plasma membrane on demand. Intracellular bicarbonate generated by luminal H secretion is removed by the basolateral anion-exchanger AE1. Chronically reduced renal acid excretion in distal renal tubular acidosis (dRTA) may lead to nephrocalcinosis and renal failure. Studies in MDCK monolayers led to the proposal of a dominant-negative trafficking mechanism to explain AE1-associated dominant dRTA. To test this hypothesis , we generated an Ae1 R607H knockin mouse, which corresponds to the most common dominant dRTA mutation in human AE1, R589H. Compared with wild-type mice, heterozygous and homozygous R607H knockin mice displayed incomplete dRTA characterized by compensatory upregulation of the Na/HCO cotransporter NBCn1. Red blood cell Ae1-mediated anion-exchange activity and surface polypeptide expression did not change. Mutant mice expressed far less Ae1 in A-ICs, but basolateral targeting of the mutant protein was preserved. Notably, mutant mice also exhibited reduced expression of V-type ATPase and compromised targeting of this proton pump to the plasma membrane upon acid challenge. Accumulation of p62- and ubiquitin-positive material in A-ICs of knockin mice suggested a defect in the degradative pathway, which may explain the observed loss of A-ICs. R607H knockin did not affect type B intercalated cells. We propose that reduced basolateral anion-exchange activity in A-ICs inhibits trafficking and regulation of V-type ATPase, compromising luminal H secretion and possibly lysosomal acidification.

Year of Publication
2017
Journal
Journal of the American Society of Nephrology : JASN
Volume
28
Issue
5
Number of Pages
1507-1520
Date Published
05/2017
ISSN Number
1533-3450
DOI
10.1681/ASN.2016020169
Alternate Journal
J. Am. Soc. Nephrol.
PMID
27932475
PMCID
PMC5407715
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