Sisplatin Uygulanan Ratlarda Oluşturulan NefrotoksisitedeMelatoninin NAMPT/SIRT-1 Sinyal Yolağı Üzerine Etkisi

Nefrotoksisite, geniş kullanım alanına sahip antineoplastik bir ilaç olan sisplatinin en yaygın yanetkisidir. Bu nedenle bir doz sisplatin alındıktan sonra renal fonksiyonlarında gerileme meydanagelen hastalarda sisplatin kullanımı %25-35 oranında kısıtlanmaktadır. Sisplatinden kaynaklanannefrotoksisite böbrekte artış gösteren oksidatif stres ile ilişkilidir. Bu çalışmada sisplatin ileoluşturulan nefrotoksisitede bir antioksidan olarak melatoninin, sisplatin kaynaklı nefrotoksisiteyekarşı biyokimyasal, histopatolojik ve moleküler düzeyde nasıl etki gösterdiğini araştırdık. Buçalışma, tek doz intraperitonal (i.p.) sisplatin uygulamasıyla oluşturulan bir rat nefrotoksisitemodelinde melatonin uygulamasının böbreklerde koruyucu etkiye sahip olduğunu göstermektedir.Melatonin verilen hayvanlarda serum üre ve kreatinin değerleri, renal bozulmanın sisplatin enjekteedilen gruba oranla belirgin biçimde azaldığını ortaya koymuştur. Böbrek dokusunda MDA ve 8-iso PGF2α seviyeleri sisplatin grubunda kontrol grubuna göre anlamlı olarak yüksek bulunmuştur.Melatonin tedavisi alan ratlarda, SIRT-1 protein ekpresyon seviyesi belirgin biçimde artış yönündedüzenlenirken NAMPT, COX-2, TGF-β1 ve TNF-α proteinlerinin ekspresyon seviyeleri iseazalmıştır. Histopatolojik bulgular; melatoninle ön tedavinin, sisplatin kaynaklı tübüler nekroz baştaolmak üzere sisplatin tarafından oluşturulan çoğu değişimi de önlediğini göstermiştir. Bu çalışmanınsonuçları, sisplatin ile oluşturulmuş böbrek hasarında melatoninin NAMPT/SIRT-1 sinyal yolağınıdüzenleyerek COX-2, TGF-β1 ve TNF-α inhibisyonu yoluyla yangıyı azaltarak bir iyileşmesağlayabildiğini göstermektedir.

The Effect of Melatonin on NAMPT/SIRT-1 Signaling Pathway on Cisplatin Induced Nephrotoxicity in Rats

Nephrotoxicity is the most relevant side effect of widely used antineoplastic drug cisplatin.Therefore use of cisplatin is limited with about 25–35% of patients experiencing a significantreduction in renal function after a single dose of cisplatin. Cisplatin-induced nephrotoxicity is relatedto an increase in oxidative stress in the kidney. In the present study, we investigated biochemically,histopathologically and at the molecular level how the melatonin display antioxidant effect againstcisplatin-induced nephrotoxicity. The present study demonstrates that the administration ofmelatonin exerts a renal protective effect in a rat model of nephrotoxicity provoked by a singleintraperitoneal (i.p.) injection of cisplatin. In the animals that receive melatonin, the levels of serumurea and creatinine indicating reduced renal injury were significantly lower as compared to thecisplatin injected group. The renal tissue MDA and 8-iso-PGF2α levels showed a significantincrease in sisplatin-treated rats compared the control rats. SIRT–1 protein expression levels weresignificantly up-regulated while NAMPT, COX-2, TGF-β1 and TNF-α protein expression level weredown-regulated in rats treated with melatonin. Histopathological findings showed that melatoninpretreatment decreased the cisplatin-induced tubular necrosis and most of the changes producedby cisplatin. Taken together, results of this study indicate that melatonin attenuates cisplatin induced nephrotoxicity by modulating NAMPT/SIRT-1 signaling, and reducing the inflammation byinhibiting COX-2, TGF-β1 and TNF-α.

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