title: (Pro)renin receptor is required for prorenin-dependent and -independent regulation of vacuolar H⁺-ATPase activity in MDCK.C11 collecting duct cells.
abstract: Prorenin binding to the prorenin receptor [(P)RR] results in nonproteolytic activation of prorenin but also directly (i.e., independent of angiotensin generation) activates signal transduction cascades that can lead to the upregulation of profibrotic factors. The (P)RR is an accessory protein of vacuolar-type H⁺-ATPase (V-ATPase) and is required for V-ATPase integrity. In addition, in collecting duct cells, prorenin-induced activation of Erk depends on V-ATPase activity. However, whether prorenin binding to the (P)RR directly regulates V-ATPase activity is as yet unknown. Here, we studied the effect of prorenin on plasma membrane V-ATPase activity in Madin-Darby canine kidney clone 11 (MDCK.C11) cells, which resemble intercalated cells of the collecting duct. Prorenin increased V-ATPase activity at low nanomolar concentrations, and the V-ATPase inhibitor bafilomycin A1, but not the angiotensin II type 1 and 2 receptor blockers irbesartan and PD-123319, prevented this. Increased, but not basal, V-ATPase activity was abolished by small interfering RNA depletion of the (P)RR. Unexpectedly, the putative peptidic (P)RR blocker handle region peptide also increased V-ATPase activity in a (P)RR-dependent manner. Finally, [Arg⁸]-vasopressin-stimulated V-ATPase activity and cAMP production were also abolished by (P)RR depletion. Our results show that in MDCK.C11 cells, the (P)RR is required for prorenin-dependent and -independent regulation of V-ATPase activity.
authors.affiliation: Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Xifeng
authors.initials: X
authors.lastname: Lu
authors.forename: Ingrid M
authors.initials: IM
authors.lastname: Garrelds
authors.forename: Carsten A
authors.initials: CA
authors.lastname: Wagner
authors.forename: A H Jan
authors.initials: AH
authors.lastname: Danser
authors.forename: Marcel E
authors.initials: ME
authors.lastname: Meima
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002021:Buffers; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007685:Kidney Tubules, Collecting / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D018942:Macrolides / Q000494:pharmacology; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology*; D012083:Renin / Q000502:physiology*; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D014162:Transfection; D014617:Vacuoles / Q000201:enzymology* / Q000378:metabolism; D014667:Vasopressins / Q000494:pharmacology; D000093342:Prorenin Receptor
chemical_list: D002021:Buffers; D004791:Enzyme Inhibitors; D018942:Macrolides; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D014667:Vasopressins; C040929:bafilomycin A1; D000242:Cyclic AMP; D012083:Renin; D006180:Proton-Translocating ATPases; D000093342:Prorenin Receptor
keywords: cAMP; diabetes; handle region peptide; kidney; renin-angiotensin system; transporter