Pioglitazone limits cyclosporine nephrotoxicity in rats
ABSTRACT Chronic cyclosporine (CsA) nephrotoxicity is a relevant factor in the pathogenesis of chronic allograft nephropathy. Pioglitazone is an agonist of PPARgamma, capable of reducing chronic inflammation. We investigated the capacity of pioglitazone in preventing renal dysfunction. Adult male Wistar rats were assigned to: Vehicle (olive oil 1 ml/kg/day), CsA (10 mg/kg/day) alone and with pioglitazone (5 or 10 mg/kg/day). The animals were sacrificed at 28 days, where blood (serum creatinine ratio, CR) and kidney samples (arteriolopathy analyses) were collected. The mRNA transcripts of TGF-beta1, PAI-1, Smad3 and 7 were evaluated by real-time PCR. As expected, CsA treatment significantly decreased renal function that peaked at day 28, compared with vehicle (CR=1.29+/-0.03 vs. 0.95+/-0.14, p<0.05). In contrast, the administration of pioglitazone 5 or 10 mg/kg combined with CsA resulted in better renal function (CR=1.09+/-0.05 and 1.14+/-0.14, respectively, p<0.05). Animals treated with CSA showed relevant arteriolopathy (49.5+/-2.86%) and pioglitazone administration significantly limited it (37.0+/-3.59% and 36.6+/-1.72%, respectively, 5 or 10 mg/kg, p<0.05). In CsA-treated animals (alone and with pioglitazone), TGF-beta1 and Smad3 increased significantly. In animals treated with CsA and pioglitazone (5 mg/kg), PAI-1 was significantly lower than CsA alone (3.96+/-0.92 vs. 7.53+/-1.38, p<0.05). Interestingly, the administration of pioglitazone 5 or 10 mg/kg was associated with an increase in Smad7 (1.79+/-0.25 and 1.75+/-0.19, respectively), compared to vehicle and to CsA-treated groups (1.08+/-0.17 and 1.17+/-0.19, respectively, p<0.05). These data provide evidence that pioglitazone acts through down regulation of pro-fibrotic cytokine PAI-1 and overexpression of the regulatory Smad7.
- SourceAvailable from: Cristiani Folharini Bortolatto
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- "Research Article Received: 13 May 2012, Revised: 21 July 2012, Accepted: 6 August 2012 Published online in Wiley Online Library: 14 September 2012 (wileyonlinelibrary.com) DOI 10.1002/jat.2818 (Pereira et al., 2006 "
ABSTRACT: Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists not only improve metabolic abnormalities of diabetes and consequent diabetic nephropathy, but they also protect against non-diabetic kidney disease in experimental models. Here, we investigated the effect of PPAR-γ agonist pioglitazone against acute renal injury on a cisplatin model in mice. Nephrotoxicity was induced by a single intraperitoneal (i.p.) injection of cisplatin (10 mg kg(-1) ). Pioglitazone was administered for six consecutive days in doses of 15 or 30 mg kg(-1) day(-1) , per os (p.o.), starting 3 days before cisplatin injection. Cisplatin treatment to mice induced a marked renal failure, characterized by a significant increase in serum urea and creatinine levels and alterations in renal tissue architecture. Cisplatin exposure induced oxidative stress as indicated by decreased levels of non-enzymatic antioxidant defenses [glutathione (GSH) and ascorbic acid levels] and components of the enzymatic antioxidant defenses [superoxide dismutase (SOD), catalase (CAT) glutathione peroxidase (GPx), glutathione reductase (GR) and and glutathione S-transferase(GST) activities)] in renal tissue. Administration of pioglitazone markedly protected against the increase in urea and creatinine levels and histological alterations in kidney induced by cisplatin treatment. Pioglitazone administration ameliorated GSH and ascorbic acid levels decreased by cisplatin exposure in mice. Pioglitazone protected against the inhibition of CAT, SOD, GPx, GR and GST activities induced by cisplatin in the kidneys of mice. These results indicated that pioglitazone has a protective effect against cisplatin-induced renal damage in mice. The protection is mediated by preventing the decline of antioxidant status. The results have implications in use of PPAR-γ agonists in human application for protecting against drugs-induced nephrotoxicity. Copyright © 2012 John Wiley & Sons, Ltd.Journal of Applied Toxicology 01/2014; 34(1). DOI:10.1002/jat.2818 · 3.17 Impact Factor
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ABSTRACT: The peroxisome proliferator-activated receptor superfamily (PPARs) comprises a class of nuclear receptors with significant effects in regulating multiple cellular pathways. Much research and clinical interest has surrounded the PPAR-gamma isoform because of its key role in the transcriptional regulation of metabolic pathways and the efficacy of thiazolidinediones, the most clinically used PPAR-gamma agonist, in the management of type 2 diabetes mellitus. In this review, we discuss the pathogenic role of PPAR-gamma in experimental models of kidney disease, clinical trials of thiazolidinediones in diabetic and non-diabetic kidney disease, recent safety concerns surrounding PPAR-gamma agonists and reflect on their potential use in 'orphan' kidney diseases.Nephron Clinical Practice 07/2009; 112(4):c230-41. DOI:10.1159/000224789 · 1.65 Impact Factor
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ABSTRACT: Individuals with systemic lupus erythematosus (SLE) have a striking increase in the risk of premature atherosclerosis, a complication preceded by significant subclinical vascular damage. A proposed mechanism leading to accelerated vascular disease in SLE is an imbalance between vascular damage and repair, as patients with this disease display significant abnormalities in phenotype and function of endothelial progenitor cells. In addition, individuals with SLE have a higher incidence of insulin resistance which may further contribute to the increased cardiovascular risk. This study examined the role of the peroxisome proliferator activated receptor gamma agonist pioglitazone in improving endothelial function, endothelial progenitor cell numbers and functional capacity, metabolic parameters, and disease activity in the lupus-prone murine model New Zealand Black/New Zealand White (NZB x NZW)F(1). Ten-week-old prenephritic female NZB/NZW F(1) mice were exposed to 10 or 25 mg/kg/day of oral pioglitazone or vehicle for 15 or 24 wk. Mice exposed to pioglitazone exhibited pronounced enhancement in endothelial-dependent vasorelaxation of thoracic aortas and in endothelial progenitor cell function, as assessed by the capacity of bone marrow-derived endothelial progenitor cells to differentiate into mature endothelial cells. Pioglitazone-treated mice showed improvement in insulin resistance, adipokine, and lipid profile. Kidneys from pioglitazone-treated mice showed significant decreases in immune complex deposition, renal inflammation, T cell glomerular infiltration, and intrarenal synthesis of TNF-alpha, IL-1beta, and VCAM-1. These results indicate that peroxisome proliferator-activated receptor gamma agonists could serve as important tools in the prevention of premature cardiovascular disease and organ damage in SLE.The Journal of Immunology 09/2009; 183(4):2729-40. DOI:10.4049/jimmunol.0804341 · 5.36 Impact Factor