title: Increased expression of (pro)renin receptor does not cause hypertension or cardiac and renal fibrosis in mice.
abstract: Binding of renin and prorenin to the (pro)renin receptor (PRR) increases their enzymatic activity and upregulates the expression of pro-fibrotic genes in vitro. Expression of PRR is increased in the heart and kidney of hypertensive and diabetic animals, but its causative role in organ damage is still unclear. To determine whether increased expression of PRR is sufficient to induce cardiac or renal injury, we generated a mouse that constitutively overexpresses PRR by knocking-in the Atp6ap2/PRR gene in the hprt locus under the control of a CMV immediate early enhancer/chicken beta-actin promoter. Mice were backcrossed in the C57Bl/6 and FVB/N strain and studied at the age of 12 months. In spite of a 25- to 80-fold renal and up to 400-fold cardiac increase in Atp6ap2/PRR expression, we found no differences in systolic blood pressure or albuminuria between wild-type and PRR overexpressing littermates. Histological examination did not show any renal or cardiac fibrosis in mutant mice. This was supported by real-time PCR analysis of inflammatory markers as well as of pro-fibrotic genes in the kidney and collagen in cardiac tissue. To determine whether the concomitant increase of renin would trigger fibrosis, we treated PRR overexpressing mice with the angiotensin receptor-1 blocker losartan over a period of 6 weeks. Renin expression increased eightfold in the kidney but no renal injury could be detected. In conclusion, our results suggest no major role for PRR in organ damage per se or related to its function as a receptor of renin.
authors.affiliation: Division of Nephrology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Alva
authors.initials: A
authors.lastname: Rosendahl
authors.affiliation: Division of Nephrology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Gianina
authors.initials: G
authors.lastname: Niemann
authors.affiliation: Division of Nephrology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Lange
authors.affiliation: Division of Nephrology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Erfan
authors.initials: E
authors.lastname: Ahadzadeh
authors.affiliation: Division of Nephrology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Krebs
authors.affiliation: 1] INSERM, U1050, Paris, France [2] Collège de France, Center for Interdisciplinary Research in Biology, Paris, France [3] CNRS, UMR 7241, College de France, Paris, France.
authors.forename: Aurelie
authors.initials: A
authors.lastname: Contrepas
authors.affiliation: Department of Pathology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Harry
authors.initials: H
authors.lastname: van Goor
authors.affiliation: Division of Nephropathology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Wiech
authors.affiliation: Max-Delbrück Center for Molecular Medicine, Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Bader
authors.affiliation: Faculty of Chemistry, Biochemistry III, University of Bielefeld, Bielefeld, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schwake
authors.affiliation: Institute of Biochemistry, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Peters
authors.affiliation: Division of Nephrology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Stahl
authors.affiliation: 1] INSERM, U1050, Paris, France [2] Collège de France, Center for Interdisciplinary Research in Biology, Paris, France [3] CNRS, UMR 7241, College de France, Paris, France.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Nguyen
authors.affiliation: Division of Nephrology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Ulrich O
authors.initials: UO
authors.lastname: Wenzel
mesh_terms: D000419:Albuminuria / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000652:urine; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D005260:Female; D005355:Fibrosis; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D057898:Hemizygote; D006579:Heterozygote; D006720:Homozygote; D006973:Hypertension / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000652:urine; D018836:Inflammation Mediators / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D019808:Losartan / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D006180:Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D051437:Renal Insufficiency / Q000139:chemically induced / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D012083:Renin / Q000737:chemistry / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D018754:Ventricular Dysfunction / Q000139:chemically induced / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D000093342:Prorenin Receptor
chemical_list: C583530:ATP6AP2 protein, mouse; D047228:Angiotensin II Type 1 Receptor Blockers; D018836:Inflammation Mediators; D011956:Receptors, Cell Surface; D012083:Renin; D006180:Proton-Translocating ATPases; D019808:Losartan; D000093342:Prorenin Receptor