Pioglitazone limits cyclosporine nephrotoxicity in rats

Laboratório de Imunologia Clínica e Experimental, Division of Nephrology, Universidade Federal de São Paulo, Escola Paulista de Medicina, São Paulo, Brazil.
International Immunopharmacology (Impact Factor: 2.47). 01/2007; 6(13-14):1943-51. DOI: 10.1016/j.intimp.2006.07.024
Source: PubMed


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.

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    • "In groups 3 and 4 the rats were pretreated with cilostazol (Otsuka Pharmaceutical Co. Ltd., Tokushima, Japan) 50 mg/kg (Cilo50) [38] and 100 mg/kg (Cilo100) [39] dose levels, respectively. The animals in groups 5 and 6 were pretreated with pioglitazone (Eli Lilly and Company, Indiana, USA) 3 mg/kg (Pio3) [40] and 10 mg/kg (Pio10) [41], respectively. Finally, animals of the last group were administered a combination of the low doses of pioglitazone and cilostazol. "
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    ABSTRACT: Cilostazol, a phosphodiesterase-III inhibitor, reportedly exhibits positive effects against ischemia/reperfusion (I/R)-induced injury in several models. However, its potential role against the renal I/R insult has not been elucidated. To test whether the PPAR-γ (of peroxisome proliferator activated receptor gamma) pathway is involved in the cilostazol effect, rats were randomized into sham, I/R, cilostazol (50 and 100 mg/kg per day, orally), pioglitazone (3 and 10 mg/kg per day, orally) and their combination at the low dose levels. Drugs regimens were administered for 14 days prior to the I/R induction. Pretreatment with cilostazol or pioglitazone provided significant protection against the I/R-induced renal injury as manifested by the attenuated serum levels of creatinine, blood urea nitrogen and cystatin C. Both drugs have also opposed the I/R-induced elevation in tissue contents/activity of neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (Κim-1), nuclear factor-κB, interleuκin-18, caspase-1, as well as malondialdehyde, iNOS, myeloperoxidase, ICAM-1 and VCAM-1. Nevertheless, the drugs increased both the PPAR-γ transcriptional activity and the content of glutathione. Furthermore, combining the two low doses of both drugs produced effects comparable to that of the high dose level of either drug, advocating the fortification of pioglitazone renoprotective effect when given concomitantly with cilostazol. In conclusion, cilostazol purveyed conceivable novel renoprotective mechanisms and alleviated incidents associated with acute renal injury either alone or in combination with pioglitazone partially via the elevation of PPAR-γ besides the amendment of the aforementioned biomarkers.
    Full-text · Article · May 2014 · PLoS ONE
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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 ( DOI 10.1002/jat.2818 (Pereira et al., 2006 "
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    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.
    Full-text · Article · Mar 2014 · Journal of Applied Toxicology
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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.
    No preview · Article · Jul 2009 · Nephron Clinical Practice
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