Activation of Peroxisome Proliferator-Activated Receptor delta Inhibits Streptozotocin-Induced Diabetic Nephropathy Through Anti-Inflammatory Mechanisms in Mice

作者：Matsushita Yuichi; Ogawa Daisuke^*; Wada Jun; Yamamoto Noriko; Shikata Kenichi; Sato Chikage; Tachibana Hiromi; Toyota Noriko; Makino Hirofumi

来源：Diabetes, 2011, 60(3): 960-968.

DOI：10.2337/db10-1361

OBJECTIVE-Activation of the nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR)-delta has been shown to improve insulin resistance, adiposity, and plasma HDL levels. Several studies have reported that activation of PPAR delta is atheroprotective; however, the role of PPAR delta in renal function remains unclear. Here, we report the renoprotective effects of PPAR delta activation in a model of streptozotocin-induced diabetic nephropathy.
RESEARCH DESIGN AND METHODS-Eight-week-old male C57BL/6 mice were divided into three groups: 1) nondiabetic control mice, 2) diabetic mice, and,9) diabetic mice treated with the PPAR delta agonist GW0742 (1 mg/kg/day). GW0742 was administered by gavage for 8 weeks after inducing diabetes.
RESULTS-GW0742 decreased urinary albumin excretion without altering blood glucose levels. Macrophage infiltration, mesangial matrix accumulation, and type IV collagen deposition were substantially attenuated by GW0742. The gene expression of inflammatory mediators in the kidney cortex, such as monocyte chemoattractant protein-1 (MCP-1) and osteopontin (OPN), was also suppressed. In vitro studies demonstrated that PPAR delta activation increased the expression of anti-inflammatory corepressor B-cell lymphoma-6, which subsequently suppressed MCP-1 and OPN expression.
CONCLUSIONS-These findings uncover a previously unrecognized mechanism for the renoprotective effects of PPAR delta agonists and support the concept that PPAR delta agonists may offer a novel therapeutic approach for the treatment of diabetic nephropathy. Diabetes 60:960-968, 2011

• 出版日期2011-3