Anti-LOX-1 therapy in rats with diabetes and dyslipidemia: ablation of renal vascular and epithelial manifestations.
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; F(1) 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 microg intravenous injection given weekly), and obese ZS rats given anti-LOX-1 rabbit antibody (OM-Ab; 2 microg 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.
Dominguez
Jesus H
JH
Department of Medicine, Indiana University School of Medicine and Indianapolis Veterans Administration Medical Center, Indianapolis, IN 46202, USA. jhdoming@iupui.edu
Mehta
Jawahar L
JL
Li
Dayuan
D
Wu
Pengfei
P
Kelly
Katherine J
KJ
Packer
C Subah
CS
Temm
Constance
C
Goss
Erin
E
Cheng
Liang
L
Zhang
Shaobo
S
Patterson
Carolyn E
CE
Hawes
John W
JW
Peterson
Richard
R
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology / Q000627:therapeutic use*; D002196:Capillaries / Q000378:metabolism / Q000503:physiopathology; D002460:Cell Line; D048909:Diabetes Complications / Q000150:complications / Q000378:metabolism; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D050171:Dyslipidemias / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism / Q000503:physiopathology; D005355:Fibrosis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D007668:Kidney / Q000098:blood supply* / Q000378:metabolism / Q000503:physiopathology*; D007687:Kidney Tubules, Proximal / Q000378:metabolism / Q000503:physiopathology; D015227:Lipid Peroxidation / Q000502:physiology; D008297:Male; D009393:Nephritis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D009765:Obesity / Q000150:complications / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D051127:Scavenger Receptors, Class E / Q000276:immunology* / Q000378:metabolism
D000888:Antibodies, Anti-Idiotypic; C495136:OLR1 protein, rat; D051127:Scavenger Receptors, Class E