Peroxisome proliferator-activated receptor α/γ dual agonist tesaglitazar attenuates diabetic nephropathy in db/db mice

Dae-Ryong Cha, Xiaoyan Zhang, Yahua Zhang, Jing Wu, Dongming Su, Young Han Jee, Xuefen Fang, Bo Yu, Matthew D. Breyer, Youfei Guan

Research output: Contribution to journalArticle

55 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2036-2045
Number of pages10
JournalDiabetes
Volume56
Issue number8
DOIs
Publication statusPublished - 2007 Aug 1
Externally publishedYes

    Fingerprint

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Cha, D-R., Zhang, X., Zhang, Y., Wu, J., Su, D., Jee, Y. H., Fang, X., Yu, B., Breyer, M. D., & Guan, Y. (2007). Peroxisome proliferator-activated receptor α/γ dual agonist tesaglitazar attenuates diabetic nephropathy in db/db mice. Diabetes, 56(8), 2036-2045. https://doi.org/10.2337/db06-1134