Submitted on January 8, 2007
Accepted on October 18, 2007
Anti-LOX-1 therapy in rats with diabetes and dyslipidemia: Ablation of renal vascular and epithelial manifestations
Jesus H. Dominguez1*, Jawahar L. Mehta2, Dayuan Li2, Pengfei Wu3, Katherine J. Kelly4, C. Subah Packer5, Constance J Temm3, Erin Goss3, Liang Cheng6, Shaobo Zhang7, Carolyn E. Patterson4, John W. Hawes8, and Richard G. Peterson9
1 Dept of Medicine and Physiology, Indiana University School of Med, Indianapolis, Indiana, United States
2 Division of Cardiovascular Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States
3 Medicine, Indiana University School of Med., Indianapolis, Indiana, United States
4 Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States
5 Department of Physiology and Biophysics, Indiana University School of Medicine, Indianapolis, Indiana, United States
6 Pathology, Indiana University Shool of Med., Indianapolis, Indiana, United States
7 Pathology, Indiana University School of Med., Indianapolis, Indiana, United States
8 Biochemistry, Miami U. of Ohio, Miami, Ohio, United States
9 Anatomy, Indiana University School of Med., Indianapolis, Indiana, United States
* To whom correspondence should be addressed. E-mail: jhdoming{at}iupui.edu.
.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 (LM) were controls, while untreated obese ZS (OM), ZS obese rats injected with non-specific 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 weeks 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.
