Anti-oxidant impact of Lisinopril and Enalapril against acute kidney injury induced by doxorubicin in male Wistar rats: involvement of kidney injury molecule-1

Abstract

Doxorubicin (DOX) is a standard anticancer agent exerting devastating effects as nephrotoxicity, hepatotoxicity and cardiotoxicity. The purpose of this study was to increase the clinical use of DOX through decreasing its detrimental effects via combination with ACE inhibitors to ameliorate the induced acute kidney injury (AKI). AKI was induced by a single injection of DOX (7.5 mg/kg; i.p.) as Group 1; control (vehicle), Group 2; DOX (7.5 mg/kg; i.p.) single dose, Group 3 and 4; Lisinopril (Lis, 20 mg/kg) and Enalapril (Enal, 40 mg/kg) orally administration for 15 consecutive days after DOX injection, respectively. Serum samples were used to measure creatinine and BUN, tissue samples were extracted to determine myeloperoxidase (MPO), malondialdehyde (MDA), total antioxidant capacity (TAC) and kidney injury molecule (KIM-1) using ELISA technique. Heme oxygenase (HO-1) RNA expression was quantified in tissue using real time polymerase chain reaction (PCR). Parts of the kidney tissue were kept in formalin for immunohistochemical demonstration of Cleaved Caspase-3 and NF-κβ immune staining and the other part was used for pathological examination. Oral treatment with Lis (20 mg/kg) and Enal (40 mg/kg) for 15 consecutive days reversed DOX effects as they reduced the serum creatinine and BUN, kidney levels of MPO and MDA, whereas the drugs increased tissue TAC. The administration of Lis and Enal with DOX also reduced KIM-1and HO-1 RNA expression. A significant decrease in cleaved caspase-3 and NF-κβ immunostainings in conjunction with pronounced amelioration in pathologies in the rat kidney were observed. We concluded that DOX adverse effects can be controlled by Lis and Enal.