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.


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 microm) 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)-1alpha, 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-1alpha mRNA expression. In contrast, expression of HIF-1alpha, 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.
Zhu
Xiang-Yang
XY
Department of Internal Medicine, Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minn 55905, USA.
Chade
Alejandro R
AR
Rodriguez-Porcel
Martin
M
Bentley
Michael D
MD
Ritman
Erik L
EL
Lerman
Amir
A
Lerman
Lilach O
LO
D000818:Animals; D005260:Female; D007672:Kidney Cortex / Q000098:blood supply* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000473:pathology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D012078:Renal Artery Obstruction / Q000097:blood* / Q000473:pathology*; D013552:Swine