title: (Pro)renin promotes fibrosis gene expression in HEK cells through a Nox4-dependent mechanism.
abstract: The (pro)renin receptor (PRR) has recently been demonstrated to bind equally well renin and its precursor, prorenin, leading to a similar intracellular signaling independent of angiotensin II. In this study, we report that human embryonic kidney cells (HEK) exposed to renin or prorenin for 24 h in the presence of a blocking concentration of the angtiotensin-converting enzyme inhibitor perindoprilate increased superoxide anion production as measured by luminescence (lucigenin) and electron spin resonance spectroscopy (hydroxylamine radical transition). Also, both renin and prorenin increased Nox4 expression while Nox2, p47(phox), and p67(phox) remained unchanged. In an investigation of the effects of renin and prorenin on fibrosis genes, it appeared that both proteins stimulated transforming growth factor-β (TGF-β), fibronectin, and plasminogen activator inhibitor type 1 (PAI-1) expression and therefore participated to an overall switch toward a profibrotic state of the kidney cells. When the cells were transfected with a siRNA targeting the PRR, Nox4 expression was efficiently prevented as well as the increase in superoxide production, TGF-β, fibronectin, and PAI-1. Finally, we demonstrated that transfection of the cells with a Nox4-specific small interfering (si) RNA also prevented fibrosis gene expression following treatment with renin or prorenin. The results demonstrate that renin and prorenin, through their specific membrane receptor and independently of angiotensin II, promote fibrosis gene expression via a Nox4-dependent mechanism.
authors.affiliation: Division of Angiology, Servier Research Institute, Suresnes, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Clavreul
authors.forename: Patricia
authors.initials: P
authors.lastname: Sansilvestri-Morel
authors.forename: Delphine
authors.initials: D
authors.lastname: Magard
authors.forename: Tony J
authors.initials: TJ
authors.lastname: Verbeuren
authors.forename: Alain
authors.initials: A
authors.lastname: Rupin
mesh_terms: D000704:Analysis of Variance; D015153:Blotting, Western; D002478:Cells, Cultured; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface / Q000378:metabolism*; D012083:Renin / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013481:Superoxides / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D000093342:Prorenin Receptor
chemical_list: D008562:Membrane Glycoproteins; D010750:Phosphoproteins; D017395:Plasminogen Activator Inhibitor 1; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D016212:Transforming Growth Factor beta; C079789:neutrophil cytosol factor 67K; D013481:Superoxides; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; C060505:neutrophil cytosolic factor 1; D012083:Renin; D000093342:Prorenin Receptor