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

• Published in: Diabetes (New York, N.Y.) Vol. 56; no. 8; pp. 2036 - 2045
• Main Authors: Cha, Dae Ryong, Zhang, Xiaoyan, Zhang, Yahua, Wu, Jing, Su, Dongming, Han, Jee Young, Fang, Xuefen, Yu, Bo, Breyer, Matthew D, Guan, Youfei
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01-08-2007
• Subjects: Adiponectin - blood; Adiponectin - genetics; Adipose Tissue - drug effects; Adipose Tissue - metabolism; Alkanesulfonates - pharmacology; Analysis; Animals; Antilipemic agents; Associated diseases and complications; Biological and medical sciences; Care and treatment; Cells, Cultured; Collagen Type I - genetics; Collagen Type IV - genetics; Diabetes. Impaired glucose tolerance; Diabetic Nephropathies - chemically induced; Diabetic Nephropathies - metabolism; Diabetic Nephropathies - pathology; Diabetic Nephropathies - physiopathology; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Gene expression; Gene Expression Regulation; Health aspects; Hypertrophy - chemically induced; Hypertrophy - pathology; Kidneys; Male; Medical sciences; Mice; Mice, Inbred C57BL; Nephrology. Urinary tract diseases; Phenylpropionates - pharmacology; PPAR alpha - agonists; PPAR alpha - genetics; PPAR alpha - metabolism; PPAR gamma - agonists; PPAR gamma - genetics; PPAR gamma - metabolism; Transcription, Genetic - genetics; Type 2 diabetes; Urinary system involvement in other diseases. Miscellaneous; China; Endocrinopathy; Kidney disease; Agonist; Urinary system disease; Diabetes mellitus; Rodentia; PPAR-α receptor; Concomitant disease; Vertebrata; Mammalia; Mouse; Animal; Diabetic nephropathy
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db06-1134

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 urea nitrogen
HOMA-IR, homeostasis model assessment of insulin resistance
MC, mesangial cell
PAS, periodic acid schiff
PPAR, peroxisome proliferator–activated receptor
PPRE, peroxisome proliferator–response element
PTC, proximal tubule cell
TGF, transforming growth factor
TZD, thiazolidinedione
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 29 May 2007. DOI: 10.2337/db06-1134.
Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db06-1134 .
Y.G. has received grant support from AstraZeneca.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted May 16, 2007.
Received August 14, 2006.
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