Published online before print June 22, 2009, doi: 10.1161/HYPERTENSIONAHA.109.128645
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(Hypertension. 2009;54:261.)
© 2009 American Heart Association, Inc.
Original Articles |
The (Pro)Renin Receptor
Site-Specific and Functional Linkage to the Vacuolar H+-ATPase in the Kidney
From the Keenan Research Centre (A.A., S.L.A., K.T., K.A.C., D.Y., J.T., M.A.K., H.L.-P., R.E.G.), Li Ka Shing Knowledge Institute, St Michael’s Hospital and University of Toronto, Toronto, Ontario, Canada; Department of Medicine (D.J.K., A.J.C.), St Vincent’s Hospital, University of Melbourne, Melbourne, Victoria, Australia; Electron Microscopy Research Services (K.E.W.), Medical School, Newcastle University, Newcastle-upon-Tyne, United Kingdom; Department of Pathology (A.M.H.), University Health Network, Toronto, Ontario, Canada.
Correspondence to Richard E. Gilbert, Keenan Research Centre of the Li Ka Shing Knowledge Institute, St Michael’s Hospital, 61 Queen St East, Toronto, Ontario, Canada M5C 2T2. E-mail richard.gilbert{at}utoronto.ca
The (pro)renin receptor ([P]RR) is a transmembrane protein that binds both renin and prorenin with high affinity, increasing the catalytic cleavage of angiotensinogen and signaling intracellularly through mitogen-activated protein kinase activation. Although initially reported as having no homology with any known membrane protein, other studies have suggested that the (P)RR is an accessory protein, named ATP6ap2, that associates with the vacuolar H+-ATPase, a key mediator of final urinary acidification. Using in situ hybridization, immunohistochemistry, and electron microscopy, together with serial sections stained with nephron segment–specific markers, we found that (P)RR mRNA and protein were predominantly expressed in collecting ducts and in the distal nephron. Within collecting ducts, the (P)RR was most abundant in microvilli at the apical surface of A-type intercalated cells. Dual-staining immunofluorescence demonstrated colocalization of the (P)RR with the B1/2 subunit of the vacuolar H+-ATPase, the ion exchanger that secretes H+ ions into the urinary space and that associates with an accessory subunit homologous to the (P)RR. In collecting duct/distal tubule lineage Madin-Darby canine kidney cells, extracellular signal–regulated kinase 1/2 phosphorylation, induced by either renin or prorenin, was attenuated by the selective vacuolar H+-ATPase inhibitor bafilomycin. The predominant expression of the (P)RR at the apex of acid-secreting cells in the collecting duct, along with its colocalization and homology with an accessory protein of the vacuolar H+-ATPase, suggests that the (P)RR may function primarily in distal nephron H+ transport, recently noted to be, at least in part, an angiotensin II–dependent phenomenon.
Key Words: (pro)renin receptor • intercalated cell • vacuolar H+-ATPase • ATP6ap2 • prorenin • renin-angiotensin system • bafilomycin
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