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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:1854.)
© 2004 American Heart Association, Inc.

Vascular Biology

Cortical Microvascular Remodeling in the Stenotic Kidney

Role of Increased Oxidative Stress

Xiang-Yang Zhu; Alejandro R. Chade; Martin Rodriguez-Porcel; Michael D. Bentley; Erik L. Ritman; Amir Lerman; Lilach O. Lerman

From the Department of Internal Medicine, Divisions of Nephrology and Hypertension (X.-Y.Z., A.R.C., L.O.L.) and Cardiovascular Diseases (M.R.P., A.L., L.O.L.), and the Department of Physiology and Biomedical Engineering (E.L.R.), Mayo Clinic, Rochester, Minn, and the Department of Biological Sciences (M.D.B.), Minnesota State University, Mankato, Minn.

Correspondence to Lilach O. Lerman, MD, PhD, Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905. E-mail lerman.lilach{at}mayo.edu

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 µm) 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, 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 mRNA expression. In contrast, expression of HIF-1, 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.

To explore the mechanisms of renal injury distal to renal artery stenosis (RAS), we studied cortical microvascular architecture in stenotic pig kidneys. We observed that antioxidant intervention improved renal growth factor expression and blunted microvascular remodeling. These findings underscore the role of increased oxidative stress in modulating intrarenal microvascular architecture in RAS.

Key Words: renal artery stenosis • oxidative stress • vascular biology • free radicals/free-radical scavenger

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