title: Renal Atp6ap2/(Pro)renin Receptor Is Required for Normal Vacuolar H+-ATPase Function but Not for the Renin-Angiotensin System.
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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche_S970, Paris Centre de Recherche Cardiovasculaire, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France.|Department of Cardio-Thoracic and Respiratory Science, Second University of Naples, Caserta, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Trepiccione
authors.affiliation: Imagine Institute, Paris Descartes University-Sorbonne Paris Cité, Paris, France.
authors.forename: Simon D
authors.initials: SD
authors.lastname: Gerber
authors.affiliation: Renal Division, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Grahammer
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche_S970, Paris Centre de Recherche Cardiovasculaire, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France.|Centro de Estudios Científicos, Valdivia, Chile.
authors.forename: Karen I
authors.initials: KI
authors.lastname: López-Cayuqueo
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche_S970, Paris Centre de Recherche Cardiovasculaire, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Baudrie
authors.affiliation: Program in Membrane Biology/Nephrology Division, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts.
authors.forename: Teodor G
authors.initials: TG
authors.lastname: Păunescu
authors.affiliation: Program in Membrane Biology/Nephrology Division, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts.
authors.forename: Diane E
authors.initials: DE
authors.lastname: Capen
authors.affiliation: Centre National de la Recherche Scientifique Equipe de Recherche Labelisée 8228, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche_S1138, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Picard
authors.affiliation: Department of Pediatrics, University of Alberta, Edmonton, Canada; and.
authors.forename: R Todd
authors.initials: RT
authors.lastname: Alexander
authors.affiliation: Renal Division, University Medical Center Freiburg, Freiburg, Germany.|BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University, Freiburg, Germany.
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Huber
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche_S970, Paris Centre de Recherche Cardiovasculaire, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France.
authors.forename: Regine
authors.initials: R
authors.lastname: Chambrey
authors.affiliation: Program in Membrane Biology/Nephrology Division, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts.
authors.forename: Dennis
authors.initials: D
authors.lastname: Brown
authors.affiliation: Program in Membrane Biology/Nephrology Division, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts.
authors.forename: Pascal
authors.initials: P
authors.lastname: Houillier
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche_S970, Paris Centre de Recherche Cardiovasculaire, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France; matias.simons@institutimagine.org dominique.eladari@inserm.fr.
authors.forename: Dominique
authors.initials: D
authors.lastname: Eladari
authors.affiliation: Imagine Institute, Paris Descartes University-Sorbonne Paris Cité, Paris, France; matias.simons@institutimagine.org dominique.eladari@inserm.fr.
authors.forename: Matias
authors.initials: M
authors.lastname: Simons
mesh_terms: D000818:Animals; D005260:Female; D007668:Kidney / Q000201:enzymology*; D008297:Male; D051379:Mice; D006180:Proton-Translocating ATPases / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000502:physiology*; D012084:Renin-Angiotensin System / Q000502:physiology*; D025262:Vacuolar Proton-Translocating ATPases / Q000502:physiology*; D000093342:Prorenin Receptor
chemical_list: D006180:Proton-Translocating ATPases; D011956:Receptors, Cell Surface; D025262:Vacuolar Proton-Translocating ATPases; C583530:ATP6AP2 protein, mouse; D000093342:Prorenin Receptor
keywords: Cell & Transport Physiology; acidosis; balance; cell biology and structure; water-electrolyte