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 language | English |
|---|---|
| Pages (from-to) | 2036-2045 |
| Number of pages | 10 |
| Journal | Diabetes |
| Volume | 56 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - 2007 Aug 1 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Internal Medicine
- Endocrinology, Diabetes and Metabolism
Cite this
Peroxisome proliferator-activated receptor α/γ dual agonist tesaglitazar attenuates diabetic nephropathy in db/db mice. / Cha, Dae-Ryong; Zhang, Xiaoyan; Zhang, Yahua; Wu, Jing; Su, Dongming; Jee, Young Han; Fang, Xuefen; Yu, Bo; Breyer, Matthew D.; Guan, Youfei.
In: Diabetes, Vol. 56, No. 8, 01.08.2007, p. 2036-2045.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Peroxisome proliferator-activated receptor α/γ dual agonist tesaglitazar attenuates diabetic nephropathy in db/db mice
AU - Cha, Dae-Ryong
AU - Zhang, Xiaoyan
AU - Zhang, Yahua
AU - Wu, Jing
AU - Su, Dongming
AU - Jee, Young Han
AU - Fang, Xuefen
AU - Yu, Bo
AU - Breyer, Matthew D.
AU - Guan, Youfei
PY - 2007/8/1
Y1 - 2007/8/1
N2 - 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.
AB - 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.
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U2 - 10.2337/db06-1134
DO - 10.2337/db06-1134
M3 - Article
C2 - 17536062
AN - SCOPUS:34547559826
VL - 56
SP - 2036
EP - 2045
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 8
ER -