Peroxisome Proliferator–Activated Receptor α/γ Dual Agonist Tesaglitazar Attenuates Diabetic Nephropathy in db/db Mice

Peroxisome Proliferator–Activated Receptor α/γ Dual Agonist Tesaglitazar Attenuates Diabetic Nephropathy in db/db Mice Dae Ryong Cha 1 , Xiaoyan Zhang 2 , Yahua Zhang 1 , Jing Wu 2 , Dongming Su 1 , Jee Young Han 1 , Xuefen Fang 1 , Bo Yu 2 , Matthew D. Breyer 1 and Youfei Guan 1 2 1 Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 2 Peking University Diabetes Center, Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China Address correspondence and reprint requests to Youfei Guan, MD, PhD, Division of Nephrology, S-3223 MCN, Vanderbilt University Medical Center, Nashville, TN 37232-2372. E-mail: youfei.guan{at}vanderbilt.edu . Or the Department of Physiology and Pathophysiology, Peking (Beijing) University Health Science Center, 38 Xueyuan Road, Beijing 100083, China. E-mail: youfeiguan{at}bjmu.edu.cn Abstract Peroxisome proliferator–activated receptors (PPARs) are nuclear transcription factors and play a central role in insulin sensitivity, lipid metabolism, and inflammation. Both PPARα and -γ are expressed in the kidney, and their agonists exhibit renoprotective effects in type 2 diabetes. In the present studies, we investigated the effect of the PPARα/γ dual agonist tesaglitazar on diabetic nephropathy in type 2 diabetic db/db mice. Treatment of db/db mice with tesaglitazar for 3 months significantly lowered fasting plasma glucose and homeostasis model assessment of insulin resistance levels but had little effect on body weight, adiposity, or cardiac function. Treatment with tesaglitazar was associated with reduced plasma insulin and total triglyceride levels and increased plasma adiponectin levels. Notably, tesaglitazar markedly attenuated albuminuria and significantly lowered glomerulofibrosis, collagen deposition, and transforming growth factor-β1 expression in renal tissues of db/db mice. In cultured mesangial cells and proximal tubule cells, where both PPARα and -γ were expressed, tesaglitazar treatment abolished high glucose–induced total collagen protein production and type I and IV collagen gene expression. Collectively, tesaglitazar treatment not only improved insulin resistance, glycemic control, and lipid profile but also markedly attenuated albuminuria and renal glomerular fibrosis in db/db mice. These findings support the utility of dual PPARα/γ agonists in treating type 2 diabetes and diabetic nephropathy. BUN, blood ur