Pioglitazone Attenuates Cardiac Fibrosis and Hypertrophy in a Rat Model of Diabetic Nephropathy

Abstract

Pioglitazone has been demonstrated to have beneficial effects on cardiovascular outcomes. However, little is known about its effect on cardiac remodeling associated with diabetic nephropathy. Therefore, this study was designed to study the effects of pioglitazone on cardiac fibrosis and hypertrophy in a rat model of diabetic nephropathy. For this purpose, male Wistar albino rats were randomly assigned into 4 groups (n = 10 per group): normal (N) group, diabetic (D) group, diabetic nephropathic (DN) group received an equal amount of vehicle (0.5% carboxy methyl cellulose), and diabetic nephropathic group treated by oral administration of pioglitazone (10 mg/kg per d) for 4 weeks. Diabetic nephropathy was induced by subtotal nephrectomy plus streptozotocin (STZ) injection. The results revealed that DN rats showed excessive deposition of collagen fibers in their cardiac tissue, along with a marked myocyte hypertrophy. This was associated with a dramatic upregulation of cardiac transforming growth factor-β1 (TGF-β1) gene. Furthermore, the gene expression of matrix metalloproteinase 2 (MMP-2) decreased, while the gene expression of tissue inhibitor of metalloproteinase 2 (TIMP-2) increased in the hearts of DN rats. In addition, enhanced lipid peroxidation and myocardial injury, evidenced by a significant increase in their serum creatine kinase-MB level were observed in DN rats. All these abnormalities were ameliorated by pioglitazone administration. Our findings suggest that upregulation of cardiac TGF-β1 gene along with the imbalance between MMP-2 and TIMP-2 expressions is critically involved in cardiac fibrosis associated with diabetic nephropathy. Pioglitazone can ameliorate cardiac remodeling by suppressing the gene expression of TGF-β1 and regulating the MMP-2/TIMP-2 system.

miRNA-711-SP1-collagen-I pathway is involved in the anti-fibrotic effect of pioglitazone in myocardial infarction

“…We speculate that the anti-fibrotic effect of pioglitazone mediated by the miR-711 pathway occurs in a PPAR-dependent manner. A vast amount of data from recent years suggested that the anti-fibrotic effects of pioglitazone mediated by PPAR occur by various mechanisms, including control of inflammation [11], cross-regulation of signaling events implicated in fibrogenesis [12][13][14], reducing oxidative stress-induced NAPDH oxidase-mediated ROS activity [13], and impacting on the key molecules involved in both inflammation or fibrosis, such as, NF-B [15]. In light of these mechanisms, the effects of the pioglitazone-miR-711 pathway on inflammatory cells, fibrogenesis, molecular signaling and ROS require further exploration.…”

Trigonella foenum-graecum water extract improves insulin sensitivity and stimulates PPAR and γ gene expression in high fructose-fed insulin-resistant rats

“… The TFG group: This group received an intragastric injection of TFG extract (1000 mg/kg/day)[ 15 ] The Pioglitazone group (Pio): This group received intragastric injection of pioglitazone (10 mg/kg/day)[ 16 ] The Diabetic control group (Con): This group was used as an insulin-resistant control group and did not receive any injections. …”

Ibuprofen Attenuates Cardiac Fibrosis in Streptozotocin-Induced Diabetic Rats

“…COX-2 inhibitors attenuated AngII-induced oxidative stress, hypertension and cardiac hypertrophy in rats [26]. Meanwhile, a specific peroxisome proliferator-activated receptor γ (PPAR-γ) ligand, such as pioglitazone, could decrease cardiac fibrosis and improve left ventricular diastolic dysfunction [27,28] by downregulating the activity of the RAS in the diabetic myocardium [29]. Therefore, increased COXs and decreased PPAR-γ could lead to cardiac fibrosis.…”