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.
"In groups 3 and 4 the rats were pretreated with cilostazol (Otsuka Pharmaceutical Co. Ltd., Tokushima, Japan) 50 mg/kg (Cilo50)  and 100 mg/kg (Cilo100)  dose levels, respectively. The animals in groups 5 and 6 were pretreated with pioglitazone (Eli Lilly and Company, Indiana, USA) 3 mg/kg (Pio3)  and 10 mg/kg (Pio10) , respectively. Finally, animals of the last group were administered a combination of the low doses of pioglitazone and cilostazol. "
[Show abstract][Hide abstract] 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.
PLoS ONE 05/2014; 9(5):e95313. DOI:10.1371/journal.pone.0095313 · 3.23 Impact Factor
"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 "
[Show abstract][Hide abstract] 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 · 1.40 Impact Factor
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