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J Am Soc Nephrol 15:1816-1825, 2004
© 2004 American Society of Nephrology

BASIC SCIENCE

Antioxidant Intervention Prevents Renal Neovascularization in Hypercholesterolemic Pigs

Alejandro R. Chade*, Michael D. Bentley§, Xiangyang Zhu*, Martin Rodriguez-Porcel{dagger}, Sara Niemeyer§, Beatriz Amores-Arriaga*, Claudio Napoli, Erik L. Ritman{ddagger}, Amir Lerman{dagger} and Lilach O. Lerman*,{dagger}

Department of Internal Medicine (Divisions of *Nephrology and Hypertension, and {dagger}Cardiovascular Diseases), and {ddagger}Physiology and Biophysics, Mayo Clinic, Rochester, §Department of Biological Sciences, Minnesota State University, Mankato, Minnesota; and Department of Medicine and Clinical Pathology–Excellence Research Center on Cardiovascular Diseases, University of Naples, Italy.

Correspondence to Dr. Lilach O. Lerman, Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Phone: 507-266-9376; Fax: 507-266-9316; E-mail: lerman.lilach{at}mayo.edu

ABSTRACT. Experimental hypercholesterolemia (HC) may lead to microvascular neovascularization, but the underlying pathogenic mechanism remains unclear. We tested the hypothesis that HC-induced intra-renal neovascularization is associated with inflammation and increased oxidative stress, and would be prevented by chronic antioxidant intervention. Kidneys were excised from pigs after a 12-wk normal (n = 10) or HC diet (n = 8), or HC diet supplemented daily with antioxidant vitamins C (1 g) and E (100 IU/kg) (HC + vitamins, n = 7). Renal cortical samples were then scanned three dimensionally with micro–computed tomography, and microvessels were counted in situ. Blood and tissue samples were removed for measurements of superoxide dismutase (SOD) activity, protein expression of the NADP(H)-oxidase subunits gp91phox, p47phox, and p67phox, vascular endothelial growth factor (VEGF) levels and mRNA, VEGF receptors (Flt-1 and Flk-1), the proinflammatory transcription factor NF{kappa}B, and the oxidized LDL receptor LOX-1. Microvascular spatial density was significantly elevated in HC compared with normal kidneys but preserved in HC + vitamins. Expression of gp91phox and p67phox was decreased in HC pigs after antioxidant intervention, and SOD improved. The increased renal expression of VEGF and Flk-1 in HC was blunted in HC + vitamins, as were the significant increases in LOX-1, NF{kappa}B, and interstitial fibrosis. This study shows that renal cortical neovascularization elicited by diet-induced HC is associated with renal inflammation, fibrosis, and upregulation of VEGF and its receptor Flk-1, likely mediated by increased endogenous oxidative stress. Chronic antioxidant supplementation may preserve the kidney in HC.




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