{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T02:40:42Z","timestamp":1760236842595,"version":"build-2065373602"},"reference-count":24,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,12,28]],"date-time":"2021-12-28T00:00:00Z","timestamp":1640649600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The prorenin\/renin receptor ((P)RR) is a multifunctional protein that is widely distributed in various organs. Despite intensive research for more than 20 years, this receptor has not been fully characterized. In this study, we generated mice overexpressing the tubular epithelial (P)RR gene ((P)RR-TG mice) to test the previously reported functional role of (P)RR by Ramkumar et al. in 2015 using tubular specific (P)RR KO mice. (P)RR-TG mice were maintained and analyzed in individual metabolic cages and were administered angiotensin II blocker (ARB), direct renin inhibitor (DRI), and bafilomycin, that is, vacuolar ATPase (V-ATPase) antagonist. (P)RR-TG mice were hypertensive and had alkalized urine with lower osmolality and Na+ excretion. ARB and DRI, but not bafilomycin, concurrently decreased blood pressure. Bafilomycin acidized urine of (P)RR-TG mice, or equivalently this phenomenon restored the effect of overexpressed transgene, suggesting that (P)RR functioned as a V-ATPase in renal tubules. Afterall, (P)RR-TG mice were mated with alternative renin transgenic mice (ARen2-TG), which we identified as intracellular renin previously, to generate double transgenic mice (DT-TG). Lethal renal tubular damage was observed in DT-TG mice, suggesting that intracellular renin may be a ligand for (P)RR in tubules. In summary, (P)RR did not substantially affect the tissue renin-angiotensin system (RAS) in our model of tubular specific (P)RR gene over-expression, but alternative intracellular renin may be involved in (P)RR signaling in addition to conventional V-ATPase function. Further investigations are warranted.<\/jats:p>","DOI":"10.3390\/ijms23010302","type":"journal-article","created":{"date-parts":[[2021,12,28]],"date-time":"2021-12-28T06:55:03Z","timestamp":1640674503000},"page":"302","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Blood Pressure Elevation of Tubular Specific (P)RR Transgenic Mice and Lethal Tubular Degeneration due to Possible Intracellular Interactions between (P)RR and Alternative Renin Products"],"prefix":"10.3390","volume":"23","author":[{"given":"Sae","family":"Saigo","sequence":"first","affiliation":[{"name":"Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3700-4358","authenticated-orcid":false,"given":"Tabito","family":"Kino","sequence":"additional","affiliation":[{"name":"Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan"},{"name":"Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kotaro","family":"Uchida","sequence":"additional","affiliation":[{"name":"Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takuya","family":"Sugawara","sequence":"additional","affiliation":[{"name":"Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8639-655X","authenticated-orcid":false,"given":"Lin","family":"Chen","sequence":"additional","affiliation":[{"name":"Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michiko","family":"Sugiyama","sequence":"additional","affiliation":[{"name":"Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5136-0730","authenticated-orcid":false,"given":"Kengo","family":"Azushima","sequence":"additional","affiliation":[{"name":"Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiromichi","family":"Wakui","sequence":"additional","affiliation":[{"name":"Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kouichi","family":"Tamura","sequence":"additional","affiliation":[{"name":"Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoaki","family":"Ishigami","sequence":"additional","affiliation":[{"name":"Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"10939","DOI":"10.1074\/jbc.273.18.10939","article-title":"Identification and characterization of a novel 9.2-kDa membrane sector-associated protein of vacuolar proton-ATPase from chromaffin granules","volume":"273","author":"Ludwig","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1172\/JCI0214276","article-title":"Pivotal role of the renin\/prorenin receptor in angiotensin II production and cellular responses to renin","volume":"109","author":"Nguyen","year":"2002","journal-title":"J. Clin. Investig."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1172\/JCI21398","article-title":"Inhibition of diabetic nephropathy by a decoy peptide corresponding to the \u201chandle\u201d region for nonproteolytic activation of prorenin","volume":"114","author":"Ichihara","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1291\/hypres.30.1139","article-title":"(Pro)renin receptor-mediated activation of mitogen-activated protein kinases in human vascular smooth muscle cells","volume":"30","author":"Sakoda","year":"2007","journal-title":"Hypertens. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1161\/01.HYP.0000240064.19301.1b","article-title":"Prorenin induces intracellular signaling in cardiomyocytes independently of angiotensin II","volume":"48","author":"Saris","year":"2006","journal-title":"Hypertension"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"R274","DOI":"10.1152\/ajpregu.00439.2005","article-title":"Renin receptor expression in human adipose tissue","volume":"292","author":"Achard","year":"2007","journal-title":"Am. J. Physiol. Integr. Comp. Physiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1093\/ajh\/hpv045","article-title":"The role of the (Pro)renin receptor in hypertensive disease","volume":"28","author":"Danser","year":"2015","journal-title":"Am. J. Hypertens."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1007\/s00424-017-2005-z","article-title":"The (pro)renin receptor and its interaction partners","volume":"469","author":"Peters","year":"2017","journal-title":"Pflug. Arch. Eur. J. Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1161\/HYPERTENSIONAHA.108.127258","article-title":"Soluble form of the (pro)renin receptor generated by intracellular cleavage by furin is secreted in plasma","volume":"53","author":"Cousin","year":"2009","journal-title":"Hypertension"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1038\/hr.2010.284","article-title":"The (pro)renin receptor is cleaved by ADAM19 in the Golgi leading to its secretion into extracellular space","volume":"34","author":"Yoshikawa","year":"2011","journal-title":"Hypertens. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1093\/jb\/mvw080","article-title":"Site-1 protease is required for the generation of soluble (pro)renin receptor","volume":"161","author":"Nakagawa","year":"2017","journal-title":"J. Biochem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1161\/CIRCRESAHA.110.224667","article-title":"The (Pro)renin receptor\/ATP6AP2 is essential for vacuolar H+-ATPase assembly in murine cardiomyocytes","volume":"107","author":"Kinouchi","year":"2010","journal-title":"Circ. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1161\/01.HYP.0000241132.48495.df","article-title":"Prorenin and its ancient receptor","volume":"48","author":"Bader","year":"2006","journal-title":"Hypertension"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1038\/sj.ki.5001627","article-title":"Increased expression of cyclooxygenase-2 in the renal cortex of human prorenin receptor gene-transgenic rats","volume":"70","author":"Kaneshiro","year":"2006","journal-title":"Kidney Int."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1038\/labinvest.2014.83","article-title":"Increased expression of (pro)renin receptor does not cause hypertension or cardiac and renal fibrosis in mice","volume":"94","author":"Rosendahl","year":"2014","journal-title":"Lab. Investig."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"105922","DOI":"10.1016\/j.phrs.2021.105922","article-title":"Functions of the (pro)renin receptor (Atp6ap2) at molecular and system levels: Pathological implications in hypertension, renal and brain development, inflammation, and fibrosis","volume":"173","author":"Hoffmann","year":"2021","journal-title":"Pharmacol. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"F48","DOI":"10.1152\/ajprenal.00126.2015","article-title":"Nephron-specific deletion of the prorenin receptor causes a urine concentration defect","volume":"309","author":"Ramkumar","year":"2015","journal-title":"Am. J. Physiol.-Ren. Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3320","DOI":"10.1681\/ASN.2015080915","article-title":"Renal Atp6ap2\/(Pro)renin receptor is required for normal vacuolar H+-ATPase function but not for the renin-angiotensin system","volume":"27","author":"Trepiccione","year":"2016","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1161\/HYPERTENSIONAHA.114.03394","article-title":"Identification of bona fide alternative renin transcripts expressed along cortical tubules and potential roles in promoting insulin resistance in vivo without significant plasma renin activity elevation","volume":"64","author":"Ishigami","year":"2014","journal-title":"Hypertension"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1242","DOI":"10.1161\/HYPERTENSIONAHA.120.14845","article-title":"Megalin a novel endocytic receptor for prorenin and renin","volume":"75","author":"Sun","year":"2020","journal-title":"Hypertension"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"41935","DOI":"10.1074\/jbc.M110.150284","article-title":"Intrarenal renin angiotensin system revisited: Role of megalin-dependent endocytosis along the proximal nephron","volume":"285","author":"Pohl","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1007\/s00424-021-02598-z","article-title":"The (pro)renin receptor (ATP6ap2) facilitates receptor-mediated endocytosis and lysosomal function in the renal proximal tubule","volume":"473","author":"Figueiredo","year":"2021","journal-title":"Pflugers Arch. Eur. J. Physiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1161\/HYPERTENSIONAHA.109.128645","article-title":"The (Pro)renin receptor: Site-specific and functional linkage to the vacuolar H+-atpase in the kidney","volume":"54","author":"Advani","year":"2009","journal-title":"Hypertension"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1152\/ajprenal.1999.277.4.F599","article-title":"Ksp-cadherin gene promoter. II. Kidney-specific activity in transgenic mice","volume":"277","author":"Igarashi","year":"1999","journal-title":"Am. J. Physiol.-Ren. 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