The prorenin receptor: what's in a name.

The discovery of the prorenin receptor, now nearly a decade ago, altered our view of the renin-angiotensin system (RAS).1,2 Binding of prorenin, the inactive precursor of renin, to the prorenin receptor results in full catalytic activity of prorenin through a nonproteolytic mechanism that likely involves a conformational change by which the prosegment moves out of the catalytic cleft, which then becomes available for the substrate, angiotensinogen. Binding of renin or prorenin (here together denoted as prorenin) to the prorenin receptor also activates intracellular signaling pathways in several cell models independent from angiotensin generation, which leads to increased cellular proliferation, cytoskeletal rearrangements, and the production of profibrotic and proinflammatory factors. Plasma prorenin levels are approximately 10-fold higher than those of renin and increase even further under certain pathologic conditions, such as diabetes mellitus complicated by nephropathy. Hence, prorenin could be a source for renin activity resulting in tissue angiotensin generation and for angiotensin-independent signaling contributing to end-organ damage by mediating fibrosis and inflammation. However, studies using the putative prorenin receptor blocker, handle region peptide, in pathologic models have yielded conflicting results.3,4 Recently, the focus has moved away from the RAS field and centered on other functions for the prorenin receptor, independent from prorenin. Different from other RAS genes, the prorenin receptor gene is an essential gene, and strategies to unravel the pathophysiological function of the prorenin receptor have therefore focused on using tissue-specific null alleles. Cardiomyocyte-specific prorenin receptor ablation results in early mortality due to heart failure.5 The cardiomyocytes of these null mice are characterized by extensive vacuolarization and impaired autophagic digestion because of decreased vacuolar-type H -ATPase (V-ATPase) activity. The carboxyterminal 8.9-kD fragment of the prorenin receptor co-purifies with the V-ATPase from bovine adrenal secretory vesicles6 and is therefore also referred to as ATP6AP2 (ATPase, H -transporting, lysosomal accessory protein 2). V-ATPases are complex proton pumps that consist of two multisubunit domains: a peripheral V1 domain that hydrolyzes ATP and a transmembrane V0 pore domain that translocates protons across membranes. V-ATPases are found in virtually every cell type and are important for acidification of intracellular compartments. In some cell types, they are abundantly expressed at the plasma membrane, for example in the intercalated cells of the collecting duct, where V-ATPases secrete protons into urine. Although not a subunit of the V-ATPase, the prorenin receptor is important for V-ATPase stability, because prorenin receptor ablation in mouse embryonic fibroblasts and in cardiomyocytes results in selective downregulation of V0, but not V1 subunits.5 The prorenin receptor is also required for canonical Wnt/ -catenin signaling, acting as a physical adaptor between the Frizzled/LDL receptor-related protein complex and V-ATPase.7 Frizzled/LDL receptor-related protein receptor complexes become internalized into signalosomes. For downstream signaling, signalosomes have to be acidified by V-ATPases, and this process depends on the presence of the prorenin receptor. In the Wnt/planar cell polarity pathway, the prorenin receptor also interacts with Frizzled receptors and is required for the planar polarization of epithelial cells.8 In the current issue of JASN, Oshima et al.9 and Riediger et al.10 report that the prorenin receptor-V-ATPase association is also essential for podocyte function and survival. Both groups crossed prorenin receptor-floxed mice with mice that express Cre-recombinase under the podocin promoter to specifically delete prorenin receptor expression in podocytes. The conditional null mice (cKO) died within 2 to 4 weeks because of renal failure. cKO mice developed nephrotic syndrome with increased serum creatinine and cholesterol levels. Albuminuria was present as early as day 2,10 indicating a defective glomerular filtration barrier. Podocytes of cKO mice displayed massive foot-process effacements accompanied by alterations in the actin cytoskeleton, whereas the slit diaphragm proteins, nephrin and podocin, showed reduced expression and redistribution to the cytosol. Over time, cKO podocytes became highly vacuolated and showed autophagic defects. Autophagy depends on V-ATPase activity, and ablation of the prorenin receptor gene from isolated podocytes concordantly resulted in deacidification of intracellular vesicles, altered actin cytoskeletal organization,10 and increased expresPublished online ahead of print. Publication date available at www.jasn.org.