Journal
EMBO MOLECULAR MEDICINE
Volume 4, Issue 10, Pages 1057-1071Publisher
WILEY
DOI: 10.1002/emmm.201201527
Keywords
deafness; distal renal tubular acidosis; H+-ATPase; kidney; proteinuria
Categories
Funding
- DFG [Hu 800/7-1]
- INSERM
- CNRS
- l'Agence Nationale de la Recherche (ANR) [ANR BLANC 2010-R10164DD]
- association pour l'information et la recherche sur les maladies renales genetiques (AIRG)
- l'ANR
- La Societe Francaise d'Hypertension Arterielle (SFHTA)
- National Institutes of Health [DK42956]
- Boston Area Diabetes and Endocrinology Research Center [NIH DK-57521]
- Center for the Study of Inflammatory Bowel Disease [NIH DK-43351]
- French Ministry of Health
- European Community [201590]
- French Tubulopathy Network
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The V-ATPase is a multisubunit complex that transports protons across membranes. Mutations of its B1 or a4 subunit are associated with distal renal tubular acidosis and deafness. In the kidney, the a4 subunit is expressed in intercalated cells of the distal nephron, where the V-ATPase controls acid/base secretion, and in proximal tubule cells, where its role is less clear. Here, we report that a4 KO mice suffer not only from severe acidosis but also from proximal tubule dysfunction with defective endocytic trafficking, proteinuria, phosphaturia and accumulation of lysosomal material and we provide evidence that these findings may be also relevant in patients. In the inner ear, the a4 subunit co-localized with pendrin at the apical side of epithelial cells lining the endolymphatic sac. As a4 KO mice were profoundly deaf and displayed enlarged endolymphatic fluid compartments mirroring the alterations in pendrin KO mice, we propose that pendrin and the proton pump co-operate in endolymph homeostasis. Thus, our mouse model gives new insights into the divergent functions of the V-ATPase and the pathophysiology of a4-related symptoms.
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