INVESTIGATION OF ANTIOXIDANT AND ANTIAPOPTOTIC EFFECTS OF LERCANIDIPINE IN DOXORUBICIN-INDUCED KIDNEY DAMAGE VIA BCL-2/BAX/SIT C/CAS-3 SIGNALING PATHWAY

Abstract

Objective Doxorubicin (Dox) is an antineoplastic drug used in chemotherapy. Nephrotoxicity is one of the important side effects that limit the use of Dox. It is known that lercanidipine (Ler), a calcium channel blocker, has antioxidant and antiapoptotic properties. In our study, we aimed to evaluate the effects of Lercanidipine (Ler) on oxidative stress and apoptosis in Dox-induced kidney damage in rats. Material and Method Twenty-four adult male rats were divided into 3 equal groups: control, Dox (20 mg/kg Dox intraperitoneally once on day 8) and Dox+Ler (20 mg/kg Dox intraperitoneally once on day 8, 2 mg/kg Ler by oral gavage every day for 10 days). At the end of the study, blood urea nitrogen (BUN) and creatinine levels were measured from the serum of rats. Also, total oxidant status (TOS), total antioxidant status (TAS) and superoxide dismutase (SOD) enzyme activity determined from kidney tissues. In addition, Bcl-2-associated X protein (Bax), B-cell-lymphoma-2 (Bcl-2) cytochrome c (sit c) and caspase-3 (Cas-3) mRNA expression levels in kidney tissue were analyzed by quantitative real time polymerase chain reaction method. Also, histopathological changes were examined by hematoxylin- eosin staining. Results In our study, Dox administration elevated BUN, creatinine, TOS and oxidative stress index, while decreasing SOD activity and TAS levels. In addition, while the expression of proapoptotic markers (Bax, sit c and Cas-3) increased in the Dox group, the expression of Bcl-2, an antiapoptotic factor, decreased. In histological examinations, findings indicating kidney damage due to Dox exposure were observed. But, the Ler administration showed protective effects by limiting all the changes related to Dox in the kidney. Conclusion Our study shows that Ler may be a potential candidate drug for preventing Dox-induced kidney damage by showing antioxidant and antiapoptotic properties.

Keywords

• Apoptosis
• Doxorubicin
• Lercanidipine
• Oxidative stress

DOKSORUBİSİN İLE OLUŞTURULAN BÖBREK HASARINDA LERKANİDİPİNİN ANTİOKSİDAN VE ANTİAPOPTOTİK ETKİLERİNİN BCL-2/BAX/SİT C/ CAS-3 YOLAĞI ÜZERİNDEN ARAŞTIRILMASI

Abstract

Amaç Doksorubisin (Dox) kemoterapide kullanılan antineoplastik bir ilaçtır. Nefrotoksisite, Dox’un kullanımını kısıtlayan önemli yan etkilerden biridir. Bir kalsiyum kanal blokeri olan lerkanidipinin (Ler) antioksidan ve antiapoptotik özellik gösterdiği bilinmektedir. Çalışmamızda, sıçanlarda oluşturulan Dox uygulaması ile tetiklenen böbrek hasarında Ler’in oksidatif stres ve apoptoz üzerine etkilerini değerlendirmeyi amaçladık. Gereç ve Yöntem Yirmi dört adet erişkin erkek sıçan; kontrol, Dox (8. günde bir kez intraperitoneal 20 mg/kg) ve Dox+Ler (8. günde bir kez intraperitoneal 20 mg/kg Dox, her gün oral gavaj ile 2 mg/kg Ler 10 gün boyunca) şeklinde 3 eşit gruba ayrılmıştır. Çalışma sonunda sakrifiye edilen sıçanların kanlarından kan üre azotu (BUN) ve kreatinin ile alınan böbrek dokusundan total oksidan seviyesi (TOS), total antioksidan seviyesi (TAS) ve süperoksid dismutaz (SOD) enzim aktivitesi ölçülmüştür. Ayrıca, böbrek dokusunda Bcl-2-ilişkili X proteini (Bax), B hücreli lenfoma-2 (Bcl-2), sitokrom c (sit c) ve kaspaz-3 (Cas-3) mRNA ekspresyon düzeyleri kantitatif gerçek zamanlı polimeraz zincir reaksiyonu yöntemiyle ölçülmüştür. Ek olarak hematoksilen-eozin boyama ile böbrekteki histopatolojik değişimler incelenmiştir. Bulgular Çalışmamızda, Dox uygulaması BUN, kreatinin, TOS ve oksidatif stres indeks seviyelerini yükseltirken, SOD aktivitesi ve TAS seviyelerini azaltmıştır. Ayrıca Dox grubunda proapoptotik belirteçlerin (Bax, sit c ve Cas-3) ekspresyonu artarken antiapoptotik bir faktör olan Bcl-2’nin ekspresyonu azalmıştır. Histolojik incelemelerde ise Dox’a bağlı böbrek hasarını gösteren bulgular gözlenmiştir. Ler uygulaması, böbrekte Dox’a bağlı tüm değişiklikleri sınırlayarak koruyucu etkiler göstermiştir. Sonuç Çalışmamız Ler’in antioksidan ve antiapoptotik özellikler göstererek Dox’un neden olduğu böbrek hasarını önlemede potansiyel bir aday olabileceğini göstermektedir.

Keywords

• Apoptoz
• Doksorubisin
• Lerkanidipin
• Oksidatif stres

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