RhoA/Rho-Kinase Contribute to the Pathogenesis of Diabetic Renal Disease

摘要: OBJECTIVE— Accumulation of glomerular matrix proteins is central to the pathogenesis diabetic nephropathy, with resident mesangial cells (MCs) known upregulate protein synthesis in response high glucose. Because activation GTPase RhoA has been implicated upregulation, we studied its role induction fibronectin MCs and vivo nephropathy. RESEARCH DESIGN AND METHODS— Glucose (30 mmol/l)-induced RhoA/Rho-kinase, AP-1 activation, upregulation were assessed by immunoblotting, luciferase, electrophoretic mobility shift assay, enzyme-linked immunosorbent real-time PCR, Northern blots, immunofluorescence. Streptozotocin-induced rats treated ρ-kinase inhibitor fasudil, which was compared enalapril, functional pathologic parameters assessed. RESULTS— led downstream Rho-kinase activation. Mannitol without effect. Activity transcription factor AP-1, increased kidneys, important profibrotic effects glucose, this dependent on signaling. Upregulation shown be mediated activator protein-1 (AP-1), prevented inhibition. siRNA dominant-negative also markedly attenuated Applicability these findings tested vivo. Fasudil sclerosis, proteinuria rats, effectiveness similar enalapril. CONCLUSIONS— High glucose activates RhoA/Rho-kinase MCs, leading induction. Inhibition pathway prevents changes supporting a potential for inhibitors RhoA/Rho treatment renal disease.