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Peroxisome proliferator activated receptor alpha/gamma dual agonist tesaglitazar attenuates diabetic nephropathy in
Dae Ryong Cha1, Xiaoyan Zhang, Yahua Zhang
1Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232-2372, USA.
Abstract:
Peroxisome proliferator-activated receptors (PPARs) are nuclear transcription factors and play a central role in insulin sensitivity, lipid metabolism, and inflammation. Both PPARalpha and -gamma 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 PPARalpha/gamma 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-beta1 expression in renal tissues of db/db mice. In cultured mesangial cells and proximal tubule cells, where both PPARalpha and -gamma 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 PPARalpha/gamma agonists in treating type 2 diabetes and diabetic nephropathy.
Insights
Tesaglitazar, a dual PPARalpha/gamma agonist, improved insulin resistance and glycemic control in diabetic mice. It also significantly reduced kidney damage markers like albuminuria and fibrosis, suggesting potential for treating type 2 diabetes and diabetic nephropathy.
Area of Science:
- Endocrinology
- Nephrology
- Metabolic Diseases
Background:
- Peroxisome proliferator-activated receptors (PPARs) are key regulators of insulin sensitivity, lipid metabolism, and inflammation.
- Both PPARalpha and PPARgamma are present in the kidney, and their activation shows protective effects in type 2 diabetes.
- Diabetic nephropathy is a major complication of type 2 diabetes, characterized by kidney damage.
Purpose of the Study:
- To investigate the renoprotective effects of the PPARalpha/gamma dual agonist tesaglitazar in a mouse model of type 2 diabetes.
- To assess tesaglitazar's impact on glycemic control, insulin resistance, and lipid metabolism.
- To evaluate tesaglitazar's effects on kidney-specific markers of damage, such as albuminuria and fibrosis.
Main Methods:
- Treatment of type 2 diabetic db/db mice with tesaglitazar for 3 months.
- Assessment of metabolic parameters including plasma glucose, insulin resistance (HOMA-IR), body weight, adiposity, and cardiac function.
- Measurement of plasma lipid profiles and adiponectin levels.
- Evaluation of renal biomarkers: albuminuria, glomerulofibrosis, collagen deposition, and transforming growth factor-beta1 (TGF-β1) expression.
- In vitro studies using cultured mesangial and proximal tubule cells to assess high glucose-induced collagen production.
Main Results:
- Tesaglitazar significantly lowered fasting plasma glucose and improved insulin resistance (HOMA-IR) without affecting body weight or cardiac function.
- Treatment led to reduced plasma insulin and triglyceride levels, alongside increased adiponectin.
- Marked attenuation of albuminuria and significant reduction in glomerulofibrosis, collagen deposition, and TGF-β1 expression in renal tissues.
- In vitro, tesaglitazar abolished high glucose-induced collagen production and gene expression in kidney cells.
Conclusions:
- Tesaglitazar demonstrates significant renoprotective effects in a type 2 diabetes mouse model by improving metabolic parameters and reducing kidney fibrosis.
- The dual PPARalpha/gamma agonist effectively attenuated albuminuria and glomerular fibrosis, indicating potential therapeutic benefits for diabetic nephropathy.
- These findings support the development of dual PPARalpha/gamma agonists as a treatment strategy for type 2 diabetes and its associated kidney complications.
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