Abstract 15223: Liver X Receptor Agonist Ameliorates Diabetic Nephropathy by Inhibiting High Glucose-Induced Osteopontin Expression
[Introduction] Osteopontin (OPN) is a proinflammatory cytokine implicated in the chemoattraction of monocytes and the development of diabetic nephropathy. Synthetic agonists for the Liver X Receptor (LXR), prevent the development of atherosclerosis by regulating cholesterol homeostasis and suppressing inflammatory gene expression, however, the role of LXR in diabetic nephropathy is poorly understood.
[Hypothesis] We assessed the hypothesis that activation of LXR ameliorates diabetic nephropathy.
[Methods] We administered LXR agonist T0901317 (10 mg/kg/day) to STZ induced-diabetic mice for 8 weeks after inducing diabetes, and evaluated the effects for diabetic nephropathy. The mechanism of OPN expression was also analyzed in mProx24 cells, a mouse renal proximal tubular epithelial cell line, stimulated with high glucose medium and pretreated with T0901317. OPN promoter activity was analyzed by transient transfection experiments with deletion series, heterologous promoter assays, and chromatin immunoprecipitation assays.
[Results] The LXR agonist T0901317 ameliorated albuminuria, glomerular mesangial expansion, and interstitial fibrosis without affecting blood glucose and triglyceride levels in STZ-induced diabetic mice. T0901317 treatment markedly decreased the expression of OPN, macrophage infiltration, and the expressions of inflammatory genes, including MCP-1, TNF-α, and TGF-β, in the diabetic kidney. Furthermore, in vitro experiments revealed that high glucose-induced OPN expression in proximal tubular epithelial cells is dependent on AP-1 binding to the proximal OPN promoter. T0901317 inhibited high glucose-induced OPN expression and negatively interfered with AP-1 binding to the proximal OPN promoter by inhibiting c-Fos and phospho-c-Jun protein expressions.
[Conclusions] In conclusion, these findings uncover a previously unrecognized mechanism for the inhibition of renal OPN expression by activation of LXR and support the concept that LXR agonists may offer a novel therapeutic approach for the treatment of diabetic nephropathy.
- © 2012 by American Heart Association, Inc.