on August 12, 2004
Published online before print August 12, 2004, doi: 10.1161/01.ATV.0000142443.52606.81
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Submitted on March 8, 2004
Accepted on August 5, 2004
Cortical Microvascular Remodeling in the Stenotic Kidney. Role of Increased Oxidative Stress
Xiang-Yang Zhu ;
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.
* To whom correspondence should be addressed. 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.
Key words: renal artery stenosis • oxidative stress • vascular biology • free radicals/free-radical scavenger
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