Anti-LOX-1 therapy in rats with diabetes and dyslipidemia: ablation of renal vascular and epithelial manifestations

Abstract

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.

Role of LOX-1 in Ang II-induced oxidative functional damage in renal tubular epithelial cells

“…ICAM-1 is a cell-surface protein typically stimulated by cytokines, cell stress, and oxidants (20,25). Dominguez et al showed that the levels of ICAM-1 which participate in leukocyte migration and epithelial dedifferentiation, were also found to be up-regulated in the tubules of diabetic obese rats and that this alteration was associated with LOX-1 expression induction (4). In the present study, the transfection with LOX-1 siRNA was able to attenuate both the Ang II-induced ICAM-1 expression and the adhesion between the monocytes and the HRPTEpiCs.…”

“…Dominguez et al have shown that obese rats, a model of metabolic syndrome in which hypertension is the dominant feature, present with renal enlargement, intense oxidative stress, lipid accumulation, leukocyte infiltration, as well as renal dysfunction and fibrosis. These rats also showed LOX-1 overexpression, and treatment with anti-LOX-1 antibody significantly limited or prevented the detrimental effects of obesity on renal function (4). In vitro, the exposure of normal rat proximal tubules to oxidized LDL (oxLDL) has been shown to markedly increase levels of LOX-1.…”

LOX-1 The Multifunctional Receptor Underlying Cardiovascular Dysfunction

“…52 The anti-LOX-1 antibody injection reduced renal inflammation and fibrosis in ZS rats. 53 Kidneys from ZS rats treated with anti-LOX-1 antibody lacked neutrophil infiltration, whereas kidneys from untreated and normal IgG-injected ZS rats had abundant clusters of neutrophils along the capillary lumens. Although anti-LOX-1 antibody did not prevent albuminuria, it increased glomerular vascular endothelial growth factor levels to help preserve renal microvascular beds.…”

“…Although anti-LOX-1 antibody did not prevent albuminuria, it increased glomerular vascular endothelial growth factor levels to help preserve renal microvascular beds. 53 It was also shown that the expression of the AT1 receptor in LOX-1 KO mice was lower than wild-type mice both before and after infusion of angiotensin II (Ang II). 54 Furthermore, Ang II-induced, but not norepinephrine-induced, blood pressure increase and renal injury were attenuated in LOX-1 KO mice compared with wild-type mice.…”

A review of molecular imaging of atherosclerosis and the potential application of dendrimer in imaging of plaque

“…oxLDL binding to LOX-1 will induce apoptosis as well as expression of adhesion molecules and MMP and activate the inflammatory pathway, all of which eventually contribute to the rupture of the plaques. [45][46][47][48] In view of high expression of LOX on more than one kind of cells concerned in AS, LOX-1 will have great potential to be a target for molecular imaging of AS plaques. At present, imaging probes targeted at LOX-1 have been developed to improve sensitivity, specificity, and biocompatibility compared to the nontargeted ones.…”