Cortical microvascular remodeling in the stenotic kidney - Role of increased oxidative stress

Objective - Mechanisms of renal injury distal to renal artery stenosis (RAS) remain unclear. We tested the hypothesis that it involves microvascular remodeling consequent to increased oxidative stress. Methods and Results - Three groups of pigs (n = 6 each) were studied after 12 weeks of RAS, RAS + antioxidant supplementation ( 100 IU/kg vitamin E and 1 g vitamin C daily), or controls. The spatial density and tortuousity of renal microvessels ( <500 mu m) were tomographically determined by 3D microcomputed tomography. The in situ production of superoxide anion and the expression of vascular endothelial growth factor (VEGF), its receptor VEGFR-2, hypoxia-inducible-factor (HIF)-1 alpha, von Hippel-Lindau (VHL) protein, and NAD(P) H oxidase (p47phox and p67phox subunits) were determined in cortical tissue. RAS and RAS + antioxidant groups had similar degrees of stenosis and hypertension. The RAS group showed a decrease in spatial density of cortical microvessels, which was normalized in the RAS + antioxidant group, as was arteriolar tortuousity. RAS kidneys also showed tissue fibrosis ( by trichrome and Sirius red staining), increased superoxide anion abundance, NAD( P) H oxidase, VHL protein, and HIF-1 alpha mRNA expression. In contrast, expression of HIF-1 alpha, VEGF, and VEGFR-2 protein was downregulated. These were all significantly improved by antioxidant intervention. Conclusions - Increased oxidative stress in the stenotic kidney alters growth factor activity and plays an important role in renal microvascular remodeling, which can be prevented by chronic antioxidant intervention.