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

Year 2022, Volume: 29 Issue: 4, 671 - 679, 27.12.2022

İlter İlhan , Halil Aşcı , Mehmer Abdulkadir Sevük , Orhan Berk İmeci , Adem Milletsever , Okan Sancer

https://doi.org/10.17343/sdutfd.1198304

Cited By: 1

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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