Pioglitazone limits cyclosporine nephrotoxicity in rats

Pereira, Maurício Galvão; Câmara, Niels Olsen Saraiva; Campaholle, Gabriella; Cenedeze, Marcos Antônio; Teixeira, Vicente de Paula Antunes; Reis, Marlene Antônia dos; Pacheco-Silva, Álvaro

doi:10.1016/j.intimp.2006.07.024

Cited by 30 publications

(16 citation statements)

References 43 publications

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“…In groups 3 and 4 the rats were pretreated with cilostazol (Otsuka Pharmaceutical Co. Ltd., Tokushima, Japan) 50 mg/kg (Cilo 50 ) [38] and 100 mg/kg (Cilo 100 ) [39] dose levels, respectively. The animals in groups 5 and 6 were pretreated with pioglitazone (Eli Lilly and Company, Indiana, USA) 3 mg/kg (Pio 3 ) [40] and 10 mg/kg (Pio 10 ) [41], respectively. Finally, animals of the last group were administered a combination of the low doses of pioglitazone and cilostazol.…”

Section: Methodsmentioning

confidence: 99%

Cilostazol Renoprotective Effect: Modulation of PPAR-γ, NGAL, KIM-1 and IL-18 Underlies Its Novel Effect in a Model of Ischemia-Reperfusion

2014

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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.

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Section: Methodsmentioning

confidence: 99%

Cilostazol Renoprotective Effect: Modulation of PPAR-γ, NGAL, KIM-1 and IL-18 Underlies Its Novel Effect in a Model of Ischemia-Reperfusion

2014

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“…70 Western blot was used to analyze the expression of collagen type I, collagen type III, fibronectin, and TGF-b1, performed as previously described. 21 Briefly, 30 mg of total protein extracted from renal tissue was denatured and separated on 8% (for collagen type I and III) or 14% (for TGF-b1) SDS-PAGE gels, and transferred to a nitrocellulose membrane by electroblotting.…”

Section: Real-time Pcr and Western Blotmentioning

confidence: 99%

Antifibrotic Effect of Tamoxifen in a Model of Progressive Renal Disease

Dellê

Rocha

Cavaglieri

et al. 2012

Journal of the American Society of Nephrology

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Tamoxifen, a selective estrogen receptor modulator, has antifibrotic properties; however, whether it can attenuate renal fibrosis is unknown. In this study, we tested the effects of tamoxifen in a model of hypertensive nephrosclerosis (chronic inhibition of nitric oxide synthesis with L-NAME). After 30 days, treated rats had significantly lower levels of albuminuria as well as lower histologic scores for glomerulosclerosis and interstitial fibrosis than untreated controls. Tamoxifen was renoprotective despite having no effect on the sustained, severe hypertension induced by L-NAME. Tamoxifen prevented the accumulation of extracellular matrix by decreasing the expression of collagen I, collagen III, and fibronectin mRNA and protein. These renoprotective effects associated with inhibition of TGF-b1 and plasminogen activator inhibitor-1, and with a significant reduction in a-smooth muscle actin-positive cells in the renal interstitium. Furthermore, tamoxifen abrogated IL-1b-and angiotensin-II-induced proliferation of fibroblasts from both kidney explants and from the NRK-49F cell line. Tamoxifen also inhibited the expression of extracellular matrix components and the production and release of TGF-b1 into the supernatant of these cells. In summary, tamoxifen exhibits antifibrotic effects in the L-NAME model of hypertensive nephrosclerosis, likely through the inhibition of TGF-b1, suggesting that it may have therapeutic use in CKD treatment.

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“…For instance, pioglitazone ameliorates biochemical (increases in plasma creatinine) and structural (arteriolopathy) signs of renal impairment caused by CSA. 17 Also, rosiglitazone, another PPARg agonist, protects against renal 41 and pancreatic 18 damaging effects of CSA. Because PPARg activation boosts the immunosuppressant effect of CSA via the inhibition of T-cell proliferation and IL-2 release, 42 the combined use of PPARg agonists and low-dose CSA might represent a rationale therapeutic approach for the prevention of CSA nephrotoxicity while maintaining adequate immunosuppression 42 and improving graft survival.…”

Section: Discussionmentioning

confidence: 99%

“…16 Recent evidence also indicates that PPARg agonists such as pioglitazone and rosiglitazone protect against CSA-induced renal injury through the regulation of profibrotic cytokines, suppression of renin-angiotensin system, and anti-inflammatory and antiapoptotic effects. [17][18][19] In this study, we asked if the inhibitory effect of CSA on renovascular reactivity to the b-adrenergic agonist isoprenaline 6,20 is modulated by PPARg. Given the intimate functional relationships between PPARg and gaseous molecules such as NO 21 and CO, 22 the investigation of the interesting possibility that nitric oxide synthase (NOS)/NO and/or heme oxygenase (HO)/CO signaling cascades contributes to the CSA-PPARg interaction constituted another prime objective of this study.…”

Section: Introductionmentioning

confidence: 99%

PPARγ Dependence of Cyclosporine–Isoprenaline Renovascular Interaction: Roles of Nitric Oxide Synthase and Heme Oxygenase

El‐Gowelli

Abd-Elrahman

Saad

et al. 2011

Journal of Cardiovascular Pharmacology

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We previously showed that cyclosporine (CSA) impairs renal vasodilations caused by β-adrenoceptor activation. This study investigated whether the peroxisome proliferator-activated receptor gamma (PPARγ) and related nitric oxide synthase (NOS)/heme oxygenase (HO) signaling mediates the CSA-β-adrenoceptor interaction. The vasodilatory response elicited by a bolus injection of isoprenaline (1 μmole) in phenylephrine-preconstricted perfused kidneys of rats was reduced after prior infusion of zinc protoporphyrin IX (ZnPP, HO inhibitor) or GW9662 (PPARγ antagonist), suggesting the involvement of PPARγ and HO-derived CO in the isoprenaline response. In contrast, the inhibition of NOS activity by N-nitro-l-arginine methyl ester had no effect on isoprenaline responses. CSA (5 μM) significantly attenuated isoprenaline vasodilations, an effect that was abolished in the presence of GW9662 and accentuated by ZnPP. Also, supplementation with the PPARγ agonist pioglitazone or with l-arginine or hemin, substrates for NOS and HO, respectively, eliminated the unfavorable effect of CSA on isoprenaline vasodilations. The protection conferred by pioglitazone against CSA-evoked attenuation of isoprenaline vasodilations was maintained in N-nitro-l-arginine methyl ester-treated kidneys and disappeared after treatment with ZnPP or GW9662. In conclusion, the activation of the HO/CO/PPARγ cascade is probably the cellular mechanism that underlies the beneficial effect of pioglitazone on the CSA-isoprenaline interaction. Further, the facilitation of the HO/CO or NOS/NO pathway seems to offset this harmful effect of CSA.

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Pioglitazone limits cyclosporine nephrotoxicity in rats

Cited by 30 publications

References 43 publications

Cilostazol Renoprotective Effect: Modulation of PPAR-γ, NGAL, KIM-1 and IL-18 Underlies Its Novel Effect in a Model of Ischemia-Reperfusion

Cilostazol Renoprotective Effect: Modulation of PPAR-γ, NGAL, KIM-1 and IL-18 Underlies Its Novel Effect in a Model of Ischemia-Reperfusion

Antifibrotic Effect of Tamoxifen in a Model of Progressive Renal Disease

PPARγ Dependence of Cyclosporine–Isoprenaline Renovascular Interaction: Roles of Nitric Oxide Synthase and Heme Oxygenase

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