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• W2917103516 abstract "The (pro)renin receptor (PRR) is a multifunctional protein that is expressed in multiple organs. Binding of prorenin/renin to the PRR activates angiotensin II–dependent and angiotensin II–independent pathways. The PRR is also involved in autophagy and Wnt/ß catenin signaling, functions that are not contingent on prorenin binding. Emerging evidence suggests that the PRR plays an important role in blood pressure regulation and glucose and lipid metabolism. Herein, we review PRR function in health and disease, with particular emphasis on hypertension and the metabolic syndrome. The (pro)renin receptor (PRR) is a multifunctional protein that is expressed in multiple organs. Binding of prorenin/renin to the PRR activates angiotensin II–dependent and angiotensin II–independent pathways. The PRR is also involved in autophagy and Wnt/ß catenin signaling, functions that are not contingent on prorenin binding. Emerging evidence suggests that the PRR plays an important role in blood pressure regulation and glucose and lipid metabolism. Herein, we review PRR function in health and disease, with particular emphasis on hypertension and the metabolic syndrome. The renin angiotensin system (RAS) plays a vital role in the maintenance of blood pressure (BP) and sodium homeostasis. In this system, circulating angiotensinogen is cleaved sequentially by renin and angiotensin-converting enzyme to generate angiotensin II (Ang II), which then modulates BP through a multitude of effects including vasoconstriction, activation of the sympathetic nervous system, increased aldosterone synthesis, and antinatriuresis.1Sparks M.A. Crowley S.D. Gurley S.B. et al.Classical renin-angiotensin system in kidney physiology.Compr Physiol. 2014; 4: 1201-1228Crossref PubMed Scopus (135) Google Scholar A number of organs contain their own RAS, wherein Ang II can exert highly localized effects.2Paul M. Poyan Mehr A. Kreutz R. Physiology of local renin-angiotensin systems.Physiol Rev. 2006; 86: 747-803Crossref PubMed Scopus (1080) Google Scholar Additional components of the RAS have now been identified3Crowley S.D. Coffman T.M. Recent advances involving the renin-angiotensin system.Exp Cell Res. 2012; 318: 1049-1056Crossref PubMed Scopus (92) Google Scholar; among these components, the (pro)renin receptor (PRR) has received much attention.4Nguyen G. Delarue F. Burckle C. et al.Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin.J Clin Invest. 2002; 109: 1417-1427Crossref PubMed Google Scholar Substantial efforts have been made to understand the localization, regulation, and function of the PRR both at a molecular and system level. Further, the recent development of PRR antagonists5Ichihara A. Hayashi M. Kaneshiro Y. et al.Inhibition of diabetic nephropathy by a decoy peptide corresponding to the “handle” region for nonproteolytic activation of prorenin.J Clin Invest. 2004; 114: 1128-1135Crossref PubMed Google Scholar, 6Li W. Sullivan M.N. Zhang S. et al.Intracerebroventricular infusion of the (Pro)renin receptor antagonist PRO20 attenuates deoxycorticosterone acetate-salt-induced hypertension.Hypertension. 2015; 65: 352-361Crossref PubMed Scopus (43) Google Scholar has advanced our understanding of the complex functions of this pleiotropic protein. Herein we review current knowledge on the biologic roles of the PRR, focusing on its involvement in hypertension and the metabolic syndrome. The PRR, encoded by the ATP6AP2 gene on the X chromosome, was first cloned in 20024Nguyen G. Delarue F. Burckle C. et al.Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin.J Clin Invest. 2002; 109: 1417-1427Crossref PubMed Google Scholar and is highly conserved across species.7Burckle C. Bader M. Prorenin and its ancient receptor.Hypertension. 2006; 48: 549-551Crossref PubMed Scopus (99) Google Scholar The full-length 350–amino-acid protein localizes to the plasma membrane and encompasses a large extracellular domain that can be cleaved to form the soluble PRR (sPRR) and a smaller transmembrane and cytoplasmic domain (M8.98Nguyen G. Muller D.N. The biology of the (pro)renin receptor.J Am Soc Nephrol. 2010; 21: 18-23Crossref PubMed Scopus (150) Google Scholar; Figure 1). The PRR has been localized to several organs including the kidney, heart, vascular smooth muscle, brain, adipose tissue, liver, eye, and placenta.4Nguyen G. Delarue F. Burckle C. et al.Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin.J Clin Invest. 2002; 109: 1417-1427Crossref PubMed Google Scholar The PRR serves a multitude of functions that depend, at least in part, on whether it is intact or cleaved into soluble and membrane/cytoplasmic components (Figure 1). Binding of prorenin to full-length PRR induces nonproteolytic activation of prorenin-mediated angiotensinogen cleavage, whereas renin bound to the PRR has 4-fold higher catalytic efficiency compared with unbound renin.4Nguyen G. Delarue F. Burckle C. et al.Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin.J Clin Invest. 2002; 109: 1417-1427Crossref PubMed Google Scholar The soluble fragment (sPRR) also binds and activates prorenin and renin. Independent of Ang II generation, prorenin/renin binding to membrane-bound full-length PRR activates intracellular signaling pathways such as mitogen-activated protein kinase (p38 MAPK) and extracellular signal-regulated kinase (ERK1/2).4Nguyen G. Delarue F. Burckle C. et al.Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin.J Clin Invest. 2002; 109: 1417-1427Crossref PubMed Google Scholar, 9Feldt S. Batenburg W.W. Mazak I. et al.Prorenin and renin-induced extracellular signal-regulated kinase 1/2 activation in monocytes is not blocked by aliskiren or the handle-region peptide.Hypertension. 2008; 51: 682-688Crossref PubMed Scopus (182) Google Scholar, 10Saris J.J. 't Hoen P.A. Garrelds I.M. et al.Prorenin induces intracellular signaling in cardiomyocytes independently of angiotensin II.Hypertension. 2006; 48: 564-571Crossref PubMed Scopus (196) Google Scholar, 11Schefe J.H. Neumann C. Goebel M. et al.Prorenin engages the (pro)renin receptor like renin and both ligand activities are unopposed by aliskiren.J Hypertens. 2008; 26: 1787-1794Crossref PubMed Scopus (82) Google Scholar PRR (M8.9) can function as an accessory subunit of the vacuolar H+ adenosine triphosphatase (ATPase) and is involved in lysosomal acidification12Ludwig J. Kerscher S. Brandt U. et al.Identification and characterization of a novel 9.2-kDa membrane sector-associated protein of vacuolar proton-ATPase from chromaffin granules.J Biol Chem. 1998; 273: 10939-10947Crossref PubMed Scopus (229) Google Scholar; this function of the PRR (M8.9) appears to be independent of prorenin/renin binding.13Lu X. Garrelds I.M. Wagner C.A. et al.(Pro)renin receptor is required for prorenin-dependent and -independent regulation of vacuolar H(+)-ATPase activity in MDCK.C11 collecting duct cells.Am J Physiol Renal Physiol. 2013; 305: F417-F425Crossref Scopus (26) Google Scholar More recently, the PRR has been reported to be involved in the Wnt/ß catenin signaling cascade with an essential role in embryonic development, cell differentiation, and metabolism.14Cruciat C.M. Ohkawara B. Acebron S.P. et al.Requirement of prorenin receptor and vacuolar H+-ATPase-mediated acidification for Wnt signaling.Science. 2010; 327: 459-463Crossref PubMed Scopus (357) Google Scholar Establishing the physiologic role of the PRR has been challenging because global or cell-specific deletion of PRR often causes early lethality or organ malformation associated with abnormal lysosomal acidification.7Burckle C. Bader M. Prorenin and its ancient receptor.Hypertension. 2006; 48: 549-551Crossref PubMed Scopus (99) Google Scholar, 15Kinouchi K. Ichihara A. Sano M. et al.The (pro)renin receptor/ATP6AP2 is essential for vacuolar H+-ATPase assembly in murine cardiomyocytes.Circ Res. 2010; 107: 30-34Crossref PubMed Scopus (199) Google Scholar, 16Oshima Y. Kinouchi K. Ichihara A. et al.Prorenin receptor is essential for normal podocyte structure and function.J Am Soc Nephrol. 2011; 22: 2203-2212Crossref PubMed Scopus (118) Google Scholar, 17Riediger F. Quack I. Qadri F. et al.Prorenin receptor is essential for podocyte autophagy and survival.J Am Soc Nephrol. 2011; 22: 2193-2202Crossref PubMed Scopus (126) Google Scholar, 18Wendling O. Champy M.F. Jaubert S. et al.Atp6ap2 ablation in adult mice impairs viability through multiple organ deficiencies.Sci Rep. 2017; 7: 9618Crossref Scopus (6) Google Scholar Cardiomyocyte-specific PRR ablation results in lethal cardiac failure within 3 weeks after birth.15Kinouchi K. Ichihara A. Sano M. et al.The (pro)renin receptor/ATP6AP2 is essential for vacuolar H+-ATPase assembly in murine cardiomyocytes.Circ Res. 2010; 107: 30-34Crossref PubMed Scopus (199) Google Scholar Podocyte-specific PRR knockout (KO) mice experience severe proteinuria and die of renal failure in the first month after birth.16Oshima Y. Kinouchi K. Ichihara A. et al.Prorenin receptor is essential for normal podocyte structure and function.J Am Soc Nephrol. 2011; 22: 2203-2212Crossref PubMed Scopus (118) Google Scholar, 17Riediger F. Quack I. Qadri F. et al.Prorenin receptor is essential for podocyte autophagy and survival.J Am Soc Nephrol. 2011; 22: 2193-2202Crossref PubMed Scopus (126) Google Scholar Collecting duct (CD)-specific PRR KO mice have pronounced apoptosis, marked renal hypoplasia, and a malformed CD system.19Song R. Preston G. Ichihara A. Yosypiv I.V. Deletion of the prorenin receptor from the ureteric bud causes renal hypodysplasia.PLoS One. 2013; 8: e63835Crossref Scopus (34) Google Scholar Loss of neuronal or adipose tissue PRR does not appear to affect organ structure or function,20Li W. Peng H. Mehaffey E.P. et al.Neuron-specific (pro)renin receptor knockout prevents the development of salt-sensitive hypertension.Hypertension. 2014; 63: 316-323Crossref PubMed Scopus (51) Google Scholar, 21Wu C.H. Mohammadmoradi S. Thompson J. et al.Adipocyte (Pro)renin-receptor deficiency induces lipodystrophy, liver steatosis and increases blood pressure in male mice.Hypertension. 2016; 68: 213-219Crossref PubMed Google Scholar, 22Shamansurova Z. Tan P. Ahmed B. et al.Adipose tissue (P)RR regulates insulin sensitivity, fat mass and body weight.Mol Metab. 2016; 5: 959-969Crossref PubMed Scopus (17) Google Scholar suggesting that the lysosomal function of the PRR is tissue specific. A recent study attempted to induce global PRR inactivation in adult mice using ROSA26-creERT2; although this model was not efficient in targeting brain, kidney, aorta, or white adipose tissue, the inducible PRR KO mice displayed early lethality, marked weight loss, hypoglycemia, and hypercholesterolemia associated with pathologic changes in the colon, bone marrow, and liver.18Wendling O. Champy M.F. Jaubert S. et al.Atp6ap2 ablation in adult mice impairs viability through multiple organ deficiencies.Sci Rep. 2017; 7: 9618Crossref Scopus (6) Google Scholar Antagonists that block prorenin from binding to the PRR have also been developed.5Ichihara A. Hayashi M. Kaneshiro Y. et al.Inhibition of diabetic nephropathy by a decoy peptide corresponding to the “handle” region for nonproteolytic activation of prorenin.J Clin Invest. 2004; 114: 1128-1135Crossref PubMed Google Scholar, 6Li W. Sullivan M.N. Zhang S. et al.Intracerebroventricular infusion of the (Pro)renin receptor antagonist PRO20 attenuates deoxycorticosterone acetate-salt-induced hypertension.Hypertension. 2015; 65: 352-361Crossref PubMed Scopus (43) Google Scholar The first PRR blocker was directed toward the handle region peptide (HRP) and prevented the binding of prorenin to the PRR; despite initial promising results,5Ichihara A. Hayashi M. Kaneshiro Y. et al.Inhibition of diabetic nephropathy by a decoy peptide corresponding to the “handle” region for nonproteolytic activation of prorenin.J Clin Invest. 2004; 114: 1128-1135Crossref PubMed Google Scholar HRP has now fallen out of favor because of partial agonistic properties.23te Riet L. van den Heuvel M. Peutz-Kootstra C.J. et al.Deterioration of kidney function by the (pro)renin receptor blocker handle region peptide in aliskiren-treated diabetic transgenic (mRen2)27 rats.Am J Physiol Renal Physiol. 2014; 306: F1179-F1189Crossref Scopus (14) Google Scholar, 24Muller D.N. Klanke B. Feldt S. et al.(Pro)renin receptor peptide inhibitor “handle-region” peptide does not affect hypertensive nephrosclerosis in Goldblatt rats.Hypertension. 2008; 51: 676-681Crossref PubMed Scopus (105) Google Scholar A newer agent, PRO20, acts as a competitive antagonist, is identical to the first 20 amino acids of the prorenin segment, and contains all of the PRR binding sites.6Li W. Sullivan M.N. Zhang S. et al.Intracerebroventricular infusion of the (Pro)renin receptor antagonist PRO20 attenuates deoxycorticosterone acetate-salt-induced hypertension.Hypertension. 2015; 65: 352-361Crossref PubMed Scopus (43) Google Scholar As discussed later, several groups have validated the specificity of PRO20 in preventing prorenin-mediated PRR function.6Li W. Sullivan M.N. Zhang S. et al.Intracerebroventricular infusion of the (Pro)renin receptor antagonist PRO20 attenuates deoxycorticosterone acetate-salt-induced hypertension.Hypertension. 2015; 65: 352-361Crossref PubMed Scopus (43) Google Scholar, 25Lu X. Wang F. Liu M. et al.Activation of ENaC in collecting duct cells by prorenin and its receptor PRR: involvement of Nox4-derived hydrogen peroxide.Am J Physiol Renal Physiol. 2016; 310: F1243-F1250Crossref PubMed Google Scholar, 26Wang F. Lu X. Liu M. et al.Renal medullary (pro)renin receptor contributes to angiotensin II-induced hypertension in rats via activation of the local renin-angiotensin system.BMC Med. 2015; 13: 278Crossref PubMed Scopus (27) Google Scholar Despite the challenges using gene targeting and PRR antagonism, as discussed in the following sections, substantial progress has been made in uncovering the physiologic and pathophysiologic roles of the PRR. The PRR has been localized to mesangial cells, podocytes, proximal tubule, distal convoluted tubule, the luminal membrane of intercalated cells, and principal cells with the highest renal expression in intercalated cells.17Riediger F. Quack I. Qadri F. et al.Prorenin receptor is essential for podocyte autophagy and survival.J Am Soc Nephrol. 2011; 22: 2193-2202Crossref PubMed Scopus (126) Google Scholar, 27Advani A. Kelly D.J. Cox A.J. et al.The (Pro)renin receptor: site-specific and functional linkage to the vacuolar H+-ATPase in the kidney.Hypertension. 2009; 54: 261-269Crossref PubMed Scopus (185) Google Scholar, 28Huang J. Siragy H.M. Glucose promotes the production of interleukine-1beta and cyclooxygenase-2 in mesangial cells via enhanced (Pro)renin receptor expression.Endocrinology. 2009; 150: 5557-5565Crossref PubMed Scopus (63) Google Scholar The CD PRR may be particularly important because prorenin is luminally secreted by the CD where it may act on the luminal PRR to stimulate sodium reabsorption and elevate BP.29Ramkumar N. Kohan D.E. Role of the collecting duct renin angiotensin system in regulation of blood pressure and renal function.Curr Hypertens Rep. 2016; 18: 29Crossref Scopus (5) Google Scholar Relevant to this, renal medullary PRR expression is enhanced in hypertensive rats (Ang II infusion and 2-kidney, 1-clip Goldblatt hypertension).30Gonzalez A.A. Lara L.S. Luffman C. et al.Soluble form of the (pro)renin receptor is augmented in the collecting duct and urine of chronic angiotensin II-dependent hypertensive rats.Hypertension. 2011; 57: 859-864Crossref PubMed Scopus (94) Google Scholar, 31Prieto M.C. Botros F.T. Kavanagh K. Navar L.G. Prorenin receptor in distal nephron segments of 2-kidney, 1-clip Goldblatt hypertensive rats.Ochsner J. 2013; 13: 26-32Google Scholar Renal medullary infusion of PRO20 reduced the hypertensive response and renal injury to Ang II infusion in rats.26Wang F. Lu X. Liu M. et al.Renal medullary (pro)renin receptor contributes to angiotensin II-induced hypertension in rats via activation of the local renin-angiotensin system.BMC Med. 2015; 13: 278Crossref PubMed Scopus (27) Google Scholar Similarly, infusion of PRR short hairpin RNA in the renal medulla decreased expression of the epithelial sodium channel (ENaC) in rats (although the effect on BP was not examined).32Quadri S. Siragy H.M. (Pro)renin receptor contributes to regulation of renal epithelial sodium channel.J Hypertens. 2016; 34: 486-494Crossref Scopus (15) Google Scholar To delineate the role of nephron PRR in BP regulation, we developed an inducible renal tubule PRR KO mouse33Ramkumar N. Stuart D. Calquin M. et al.Nephron-specific deletion of the prorenin receptor causes a urine concentration defect.Am J Physiol Renal Physiol. 2015; 309: F48-F56Crossref Scopus (33) Google Scholar to avoid the deleterious effects of PRR deletion on organ development. Renal tubule PRR KO mice had similar BP as control mice under varying sodium intake but had an attenuated hypertensive response with reduced renal ENaC expression after Ang II infusion.34Ramkumar N. Stuart D. Mironova E. et al.Renal tubular epithelial cell prorenin receptor regulates blood pressure and sodium transport.Am J Physiol Renal Physiol. 2016; 311: F186-F194Crossref Scopus (21) Google Scholar Further, prorenin stimulated ENaC activity in acutely isolated cortical CD in control mice but not in renal tubule PRR KO mice.34Ramkumar N. Stuart D. Mironova E. et al.Renal tubular epithelial cell prorenin receptor regulates blood pressure and sodium transport.Am J Physiol Renal Physiol. 2016; 311: F186-F194Crossref Scopus (21) Google Scholar Two other mouse models with CD-specific PRR deletion recapitulated the protective effects of PRR deletion on Ang II–induced hypertension and ENaC expression.35Peng K. Lu X. Wang F. et al.Collecting duct (pro)renin receptor targets ENaC to mediate angiotensin II-induced hypertension.Am J Physiol Renal Physiol. 2017; 312: F245-F253Crossref Scopus (21) Google Scholar, 36Prieto M.C. Reverte V. Mamenko M. et al.Collecting duct prorenin receptor knockout reduces renal function, increases sodium excretion, and mitigates renal responses in ANG II-induced hypertensive mice.Am J Physiol Renal Physiol. 2017; 313: F1243-F1253Crossref Scopus (15) Google Scholar In contrast, Trepiccione et al.37Trepiccione F. Gerber S.D. Grahammer F. et al.Renal Atp6ap2/(Pro)renin receptor is required for normal vacuolar H+-ATPase function but not for the renin-angiotensin system.J Am Soc Nephrol. 2016; 27: 3320-3330Crossref PubMed Scopus (44) Google Scholar observed no differences in BP, sodium excretion, or ENaC expression following Ang II infusion in their nephron wide PRR KO mouse model compared with control subjects. Instead, the authors observed reduced ability to excrete an acid load, blunted vacuolar H+-ATPase activity and expression, and increased renal medullary lysosomal protein and autophagosome markers.37Trepiccione F. Gerber S.D. Grahammer F. et al.Renal Atp6ap2/(Pro)renin receptor is required for normal vacuolar H+-ATPase function but not for the renin-angiotensin system.J Am Soc Nephrol. 2016; 27: 3320-3330Crossref PubMed Scopus (44) Google Scholar One explanation for the discordant findings may be related to the high dose of Ang II used to induce hypertension (1000 ng/kg/min in the latter study vs. 300–600 ng/kg/min in others), as well as the timing of PRR deletion (prenatal in the study by Trepiccione et al.37Trepiccione F. Gerber S.D. Grahammer F. et al.Renal Atp6ap2/(Pro)renin receptor is required for normal vacuolar H+-ATPase function but not for the renin-angiotensin system.J Am Soc Nephrol. 2016; 27: 3320-3330Crossref PubMed Scopus (44) Google Scholar vs. during adulthood in other studies). Renal tubular PRR also modulates water reabsorption through Ang II–dependent and Ang II–independent mechanisms.33Ramkumar N. Stuart D. Calquin M. et al.Nephron-specific deletion of the prorenin receptor causes a urine concentration defect.Am J Physiol Renal Physiol. 2015; 309: F48-F56Crossref Scopus (33) Google Scholar, 37Trepiccione F. Gerber S.D. Grahammer F. et al.Renal Atp6ap2/(Pro)renin receptor is required for normal vacuolar H+-ATPase function but not for the renin-angiotensin system.J Am Soc Nephrol. 2016; 27: 3320-3330Crossref PubMed Scopus (44) Google Scholar, 38Lu X. Wang F. Xu C. et al.Soluble (pro)renin receptor via beta-catenin enhances urine concentration capability as a target of liver X receptor.Proc Natl Acad Sci U S A. 2016; 113: E1898-E1906Crossref PubMed Google Scholar, 39Wang F. Lu X. Peng K. et al.Antidiuretic action of collecting duct (pro)renin receptor downstream of vasopressin and PGE2 receptor EP4.J Am Soc Nephrol. 2016; 27: 3022-3034Crossref Scopus (27) Google Scholar Recent studies have shown that the PRR regulates vasopressin-stimulated AQP2 expression via activation of prostaglandin EP4 receptor39Wang F. Lu X. Peng K. et al.Antidiuretic action of collecting duct (pro)renin receptor downstream of vasopressin and PGE2 receptor EP4.J Am Soc Nephrol. 2016; 27: 3022-3034Crossref Scopus (27) Google Scholar and the Wnt/β-catenin pathway.38Lu X. Wang F. Xu C. et al.Soluble (pro)renin receptor via beta-catenin enhances urine concentration capability as a target of liver X receptor.Proc Natl Acad Sci U S A. 2016; 113: E1898-E1906Crossref PubMed Google Scholar A fundamental question is whether the intercalated and/or principal cell PRR modulates renal sodium and water reabsorption. To address this question, we developed mice with principal or intercalated cell-specific deletion of the PRR.40Ramkumar N. Stuart D. Mironova E. et al.Collecting duct principal, but not intercalated, cell prorenin receptor regulates renal sodium and water excretion.Am J Physiol Renal Physiol. 2018; 315: F607-F617Crossref Scopus (7) Google Scholar Although loss of the PRR selectively in intercalated cells resulted in lower body weight, we found no effect on renal histology, medullary ENaC or aquaporin-2 expression, urine-concentrating ability, or prorenin-stimulated ENaC activity by isolated CD. In contrast, principal cell-specific PRR deletion reduced ENaC and AQP2 expression in the renal medulla, decreased urine-concentrating ability, and abolished prorenin-stimulated ENaC activity in isolated CD. Thus these studies indicate that principal but not intercalated cell PRR modulates renal sodium and water transport. The macula densa PRR also appears to regulate BP and systemic renin release.41Riquier-Brison A.D.M. Sipos A. Prokai A. et al.The macula densa prorenin receptor is essential in renin release and blood pressure control.Am J Physiol Renal Physiol. 2018; 315: F521-F534Crossref PubMed Scopus (6) Google Scholar Using a combination of cell culture and in vivo studies, Riquier-Brison et al.41Riquier-Brison A.D.M. Sipos A. Prokai A. et al.The macula densa prorenin receptor is essential in renin release and blood pressure control.Am J Physiol Renal Physiol. 2018; 315: F521-F534Crossref PubMed Scopus (6) Google Scholar demonstrated that the macula densa PRR amplifies renin/prorenin-stimulated renin release via ERK1/2 signaling in a short-loop feed forward mechanism. Consistent with this finding, mice with macula densa–specific PRR ablation have reduced BP and plasma renin levels; these effects were more prominent after treatment with a low-salt diet and RAS blockers.41Riquier-Brison A.D.M. Sipos A. Prokai A. et al.The macula densa prorenin receptor is essential in renin release and blood pressure control.Am J Physiol Renal Physiol. 2018; 315: F521-F534Crossref PubMed Scopus (6) Google Scholar The renal PRR also may contribute to the development of hypertension in kidney disease. Mice heterozygous for PRR deletion in nephron progenitor cells (homozygous deletion leads to early neonatal death) have fewer glomeruli and altered glomerular basement membrane ultrastructure and experience develop hypertension at 2 months of age,42Song R. Kidd L. Janssen A. Yosypiv I.V. Conditional ablation of the prorenin receptor in nephron progenitor cells results in developmental programming of hypertension.Physiol Rep. 2018; 6: e13644Crossref Scopus (7) Google Scholar suggesting that early loss of PRR may be involved in developmental programming of hypertension. Recently, Xu et al.43Xu C. Lu A. Lu X. et al.Activation of renal (pro)renin receptor contributes to high fructose-induced salt sensitivity.Hypertension. 2017; 69: 339-348Crossref PubMed Scopus (20) Google Scholar found increased renal PRR expression, activation of the intrarenal RAS, and salt-sensitive hypertension in rats fed a high-fructose diet; treatment with PRO20 reduced high-fructose–induced sodium retention, BP, and intrarenal RAS activation. Polycystic kidney disease is associated with early onset of hypertension, and an animal model of polycystic kidney disease had increased renin expression in cysts and mislocalization of the PRR from the luminal membrane of intercalated cells to the basolateral membrane of principal cells.44Saigusa T. Dang Y. Bunni M.A. et al.Activation of the intrarenal renin-angiotensin-system in murine polycystic kidney disease.Physiol Rep. 2015; 3Crossref PubMed Scopus (21) Google Scholar However, despite growing evidence for the renal PRR in BP regulation and renal function, some inconsistencies exist. Overexpression of the PRR under the control of cytomegalovirus early enhancer/chicken ß-actin promoter (expressed in embryonic stem cells) in mice does not alter BP or albuminuria despite a 25- to 80-fold increase in renal PRR expression.45Rosendahl A. Niemann G. Lange S. et al.Increased expression of (pro)renin receptor does not cause hypertension or cardiac and renal fibrosis in mice.Lab Invest. 2014; 94: 863-872Crossref Scopus (18) Google Scholar Conversely, transgenic rats with ubiquitous human PRR overexpression remain normotensive despite proteinuria and progressive nephropathy.46Kaneshiro Y. Ichihara A. Sakoda M. et al.Slowly progressive, angiotensin II-independent glomerulosclerosis in human (pro)renin receptor-transgenic rats.J Am Soc Nephrol. 2007; 18: 1789-1795Crossref PubMed Scopus (190) Google Scholar Taken together, these studies raise the possibility that whereas general PRR overexpression may not affect BP, specific renal cell (particularly the CD) PRR is involved in BP regulation, particularly under pathophysiologic conditions (Figure 2). Cardiac myocyte PRR is closely linked to the vacuolar H⁺-ATPase, as well as the ryanodine receptor.47Connelly K.A. Advani A. Kim S. et al.The cardiac (pro)renin receptor is primarily expressed in myocyte transverse tubules and is increased in experimental diabetic cardiomyopathy.J Hypertens. 2011; 29: 1175-1184Crossref Scopus (24) Google Scholar Cardiac PRR expression is increased in diabetes,47Connelly K.A. Advani A. Kim S. et al.The cardiac (pro)renin receptor is primarily expressed in myocyte transverse tubules and is increased in experimental diabetic cardiomyopathy.J Hypertens. 2011; 29: 1175-1184Crossref Scopus (24) Google Scholar myocardial infarction,48Mahmud H. Candido W.M. van Genne L. et al.Cardiac function and architecture are maintained in a model of cardiorestricted overexpression of the prorenin-renin receptor.PLoS One. 2014; 9: e89929Crossref Scopus (7) Google Scholar and heart failure.49Hirose T. Mori N. Totsune K. et al.Gene expression of (pro)renin receptor is upregulated in hearts and kidneys of rats with congestive heart failure.Peptides. 2009; 30: 2316-2322Crossref PubMed Scopus (50) Google Scholar In addition, high sodium intake and severe sodium restriction modulate cardiac PRR expression.50Hayakawa Y. Aoyama T. Yokoyama C. et al.High salt intake damages the heart through activation of cardiac (pro) renin receptors even at an early stage of hypertension.PLoS One. 2015; 10: e0120453Crossref Scopus (21) Google Scholar Rats fed a high-salt diet (8.9% sodium) had elevated BP and cardiac fibrosis associated with enhanced cardiac expression of prorenin/renin and the PRR.50Hayakawa Y. Aoyama T. Yokoyama C. et al.High salt intake damages the heart through activation of cardiac (pro) renin receptors even at an early stage of hypertension.PLoS One. 2015; 10: e0120453Crossref Scopus (21) Google Scholar Similarly, very low salt intake (0.01% sodium) in rats increased cardiac expression of prorenin/renin and the PRR and accelerated cardiac and perivascular fibrosis despite normal blood pressure.51Okamoto C. Hayakawa Y. Aoyama T. et al.Excessively low salt diet damages the heart through activation of cardiac (pro) renin receptor, renin-angiotensin-aldosterone, and sympatho-adrenal systems in spontaneously hypertensive rats.PLoS One. 2017; 12: e0189099Crossref Scopus (7) Google Scholar The in vivo role of cardiac PRR in hypertension and cardiac function has been difficult to determine because, as previously mentioned, constitutive deletion of the PRR in the cardiomyocytes leads to lethal heart failure as a result of impaired lysosomal function.15Kinouchi K. Ichihara A. Sano M. et al.The (pro)renin receptor/ATP6AP2 is essential for vacuolar H+-ATPase assembly in murine cardiomyocytes.Circ Res. 2010; 107: 30-34Crossref PubMed Scopus (199) Google Scholar Global or cardiospecific overexpression of the PRR did not alter BP or cardiac structure or function at baseline46Kaneshiro Y. Ichihara A. Sakoda M. et al.Slowly progressive, angiotensin II-independent glomerulosclerosis in human (pro)renin receptor-transgenic rats.J Am Soc Nephrol. 2007; 18: 1789-1795Crossref PubMed Scopus (190) Google Scholar, 48Mahmud H. Candido W.M. van Genne L. et al.Cardiac function and architecture are maintained in a model" @default.
• W2917103516 created "2019-03-02" @default.
• W2917103516 creator A5075086560 @default.
• W2917103516 creator A5089908331 @default.
• W2917103516 date "2019-05-01" @default.
• W2917103516 modified "2023-09-30" @default.
• W2917103516 title "The (pro)renin receptor: an emerging player in hypertension and metabolic syndrome" @default.
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