title: Receptor-dependent prorenin activation and induction of PAI-1 expression in vascular smooth muscle cells.
abstract: Although elevated plasma prorenin levels are commonly found in diabetic patients and correlate with microvascular complications, the pathological role of these increases, if any, remains unclear. Prorenin/renin binding to the prorenin/renin receptor [(p)RR] enhances the efficiency of angiotensinogen cleavage by renin and unmasks prorenin catalytic activity. We asked whether plasma prorenin could be activated in local vascular tissue through receptor binding. Immunohistochemical staining showing localization of the (p)RR in the aorta to vascular smooth muscle cells (VSMCs). After cultured rat VSMCs were incubated with 10(-7) M inactive prorenin, cultured supernatant acquired the ability to generate ANG I from angiotensinogen, indicating that prorenin had been activated. Activated prorenin facilitated angiotensin generation in cultured VSMCs when exogenous angiotensinogen was added. Small interfering RNA (siRNA) against the (p)RR blocked this activation and subsequent angiotensin generation. Prorenin alone induced dose- and time-dependent increases in mRNA and protein for the profibrotic molecule plasminogen activator inhibitor (PAI)-1, effects that were blocked by siRNA, but not by the ANG II receptor antagonist saralasin. When inactive prorenin and angiotensinogen were incubated with cells, PAI-1 mRNA increased a striking 54-fold, 8-fold higher than the increase seen with prorenin alone. PAI-1 protein increased 2.75-fold. These effects were blocked by treatment with siRNA + saralasin. We conclude that prorenin at high concentration binds the (p)RR on VSMCs and is activated. This activation leads to increased expression of PAI-1 via ANG II-independent and -dependent mechanisms. These data provide a mechanism by which elevated prorenin levels in diabetes may contribute to the progression of fibrotic disease.
authors.affiliation: Fibrosis Research Laboratory, Division of Nephrology, Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah 84103, USA.
authors.forename: Jiandong
authors.initials: J
authors.lastname: Zhang
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Noble
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Border
authors.forename: Rick T
authors.initials: RT
authors.lastname: Owens
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000804:Angiotensin II / Q000502:physiology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000737:chemistry / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000502:physiology; D007150:Immunohistochemistry; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000201:enzymology / Q000378:metabolism*; D009392:Nephrectomy; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis* / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000502:physiology*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000302:isolation & purification; D012083:Renin / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012504:Saralasin / Q000494:pharmacology; D000093342:Prorenin Receptor
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D017395:Plasminogen Activator Inhibitor 1; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D000804:Angiotensin II; D012083:Renin; D012504:Saralasin; D000093342:Prorenin Receptor