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Am J Physiol Renal Physiol 294: F110-F119, 2008. First published November 7, 2007; doi:10.1152/ajprenal.00013.2007
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Anti-LOX-1 therapy in rats with diabetes and dyslipidemia: ablation of renal vascular and epithelial manifestations

Jesus H. Dominguez,2 Jawahar L. Mehta,1 Dayuan Li,1 Pengfei Wu,2 Katherine J. Kelly,2 C. Subah Packer,3 Constance Temm,4 Erin Goss,2 Liang Cheng,4 Shaobo Zhang,4 Carolyn E. Patterson,2 John W. Hawes,5 and Richard Peterson6

Departments of 2Medicine, 3Physiology, 4Pathology, 5Biochemistry and Molecular Biology, and 6Anatomy, Indiana University School of Medicine and Indianapolis Veterans Administration Medical Center, Indianapolis, Indiana; and the 1Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas

Submitted 8 January 2007 ; accepted in final form 18 October 2007

LOX-1 is a multifunctional membrane receptor that binds and internalizes oxidized LDL (oxLDL). We tested the hypothesis that blockade of LOX-1 with an anti-LOX-1 antibody limits nephropathy in male rats with diabetes and dyslipidemia (ZS rats; F1 hybrid product of Zucker fatty diabetic rats and spontaneous hypertensive heart failure rats). Lean ZS rats were controls, while untreated obese ZS (OM), ZS obese rats injected with nonspecific rabbit IgG (OM-IgG; 2 µg intravenous injection given weekly), and obese ZS rats given anti-LOX-1 rabbit antibody (OM-Ab; 2 µg intravenous injection given weekly) were the experimental groups. The rats were treated from 6 to 21 wk of age. All obese groups had severe dyslipidemia and hyperglycemia. Kidneys of obese rats expressed LOX-1 in capillaries and tubules, were larger, accumulated lipid, had intense oxidative stress, leukocyte infiltration, depressed mitochondrial enzyme level and function, and peritubular fibrosis (all P < 0.05 vs. lean ZS rats). Injections with LOX-1 antibody limited these abnormalities (P < 0.01 vs. data in OM or OM-lgG rats). In vitro, renal epithelial LOX-1 expression was verified in a cultured proximal tubule cell line. Our study indicates that anti-LOX-1 (vascular and epithelial) therapy may effectively reverse critical pathogenic elements of nephropathy in diabetes and dyslipidemia.

renal failure; diabetic nephropathies; atherosclerosis


Address for reprint requests and other correspondence: J. H. Dominguez, VAMC, Nephrology, N 111, 1481 W. 10th St., Indianapolis, IN 46202 (e-mail: jhdoming{at}iupui.edu)






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