Abstract
Pioglitazone is a type of peroxisome proliferator-activated receptor γ (PPARγ) agonist and has been demonstrated to be effective in chronic kidney diseases (CKD) treatment. However, the underlying mechanism involved in the renoprotection of pioglitazone has not been fully revealed. In the present study, the renoprotective mechanism of pioglitazone was investigated in 5/6 nephrectomized (Nx) rats and TGF-β1-exposed HK-2 cells. Pioglitazone attenuated renal injury and improved renal function, as examined by 24 h urinary protein, blood urea nitrogen and plasma creatinine in Nx rats. Renal fibrosis and enhanced expressions of profibrotic proteins TGF-β1, fibronectin and collagen I caused by Nx were significantly alleviated by pioglitazone. In addition, pioglitazone protected mitochondrial functions by stabilizing the mitochondrial membrane potential, inhibiting ROS generation, maintaining ATP production and the activities of complexes I and III, and preventing cytochrome C leakage from mitochondria. Pioglitazone also upregulated the expression levels of ATP synthase β, COX I and NDUFB8, which were downregulated in the kidney of Nx rats and TGF-β1-exposed HK-2 cells. Furthermore, pioglitazone increased fusion proteins Opa-1 and Mfn2 expressions and decreased fission protein Drp1 expression. The results imply that pioglitazone may exert the renoprotective effects through modulating mitochondrial electron transport chain and mitochondrial dynamics in CKD. Finally, these recoveries were completely or partly inhibited by GW9662, which suggests that these effects at least partly PPARγ dependent. This study provides evidence for the pharmacological mechanism of pioglitazone in the treatment of CKD.
Highlights
Chronic renal failure (CRF), characterized by glomerulosclerosis and interstitial fibrosis, is the common end stage of all kinds of chronic kidney diseases (CKDs)
In the kidney of Nx rats, serious glomerular sclerosis and tubulointerstitial fibrosis were found. These injuries were attenuated after pioglitazone treatment, PPAR γ inhibitor GW9662 blocked the effects of pioglitazone
The present study demonstrated that peroxisome proliferator-activated receptor γ (PPARγ) agonist pioglitazone attenuated renal injury and tubulointerstitial fibrosis evidenced by the improved renal functions, reduced fibrotic areas and downregulated profibrotic proteins
Summary
Chronic renal failure (CRF), characterized by glomerulosclerosis and interstitial fibrosis, is the common end stage of all kinds of chronic kidney diseases (CKDs). Transforming growth factor-β1 (TGF-β1), an extensively studied profibrogenic cytokine, plays an important role in renal fibrosis in CKD (Wang et al, 2005; Lopez-Hernandez and Lopez-Novoa, 2012). It promotes fibrosis through several actions including increasing extracellular matrix (ECM) synthesis, decreasing ECM degradation, activating resident myofibroblast and inducing epithelial to mesenchymal transition (EMT) and inflammation (Lopez-Hernandez and Lopez-Novoa, 2012). As an organ with great demand of energy, kidney is abundant in mitochondria and mitochondrial dysfunction is one of the major factors in the pathogenesis of renal injury (de Cavanagh et al, 2007; Yuan et al, 2012). Mitochondria may be a potent target for CKD treatment
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