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Renal Atp6ap2/(Pro)renin Receptor Is Required for Normal Vacuolar H+-ATPase Function but Not for the Renin-Angiotensin System.

Authors
  • Trepiccione, Francesco
  • Gerber, Simon D
  • Grahammer, Florian
  • López-Cayuqueo, Karen I
  • Baudrie, Véronique
  • Păunescu, Teodor G
  • Capen, Diane E
  • Picard, Nicolas
  • Alexander, R Todd
  • Huber, Tobias B
  • Chambrey, Regine
  • Brown, Dennis
  • Houillier, Pascal
  • Eladari, Dominique
  • Simons, Matias
Type
Published Article
Journal
Journal of the American Society of Nephrology
Publisher
American Society of Nephrology (ASN)
Publication Date
Apr 07, 2016
Volume
27
Issue
11
Pages
3320–3330
Identifiers
DOI: 10.1681/asn.2015080915
PMID: 27044666
PMCID: PMC5084887
Source
USPC - SET - SVS
Keywords
License
Green

Abstract

ATPase H+-transporting lysosomal accessory protein 2 (Atp6ap2), also known as the (pro)renin receptor, is a type 1 transmembrane protein and an accessory subunit of the vacuolar H+-ATPase (V-ATPase) that may also function within the renin-angiotensin system. However, the contribution of Atp6ap2 to renin-angiotensin-dependent functions remains unconfirmed. Using mice with an inducible conditional deletion of Atp6ap2 in mouse renal epithelial cells, we found that decreased V-ATPase expression and activity in the intercalated cells of the collecting duct impaired acid-base regulation by the kidney. In addition, these mice suffered from marked polyuria resistant to desmopressin administration. Immunoblotting revealed downregulation of the medullary Na+-K+-2Cl- cotransporter NKCC2 in these mice compared with wild-type mice, an effect accompanied by a hypotonic medullary interstitium and impaired countercurrent multiplication. This phenotype correlated with strong autophagic defects in epithelial cells of medullary tubules. Notably, cells with high accumulation of the autophagosomal substrate p62 displayed the strongest reduction of NKCC2 expression. Finally, nephron-specific Atp6ap2 depletion did not affect angiotensin II production, angiotensin II-dependent BP regulation, or sodium handling in the kidney. Taken together, our results show that nephron-specific deletion of Atp6ap2 does not affect the renin-angiotensin system but causes a combination of renal concentration defects and distal renal tubular acidosis as a result of impaired V-ATPase activity.

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