Protective side of Nebivolol via Akt/Hif-1α/eNOS signaling pathway: Nephrotoxicity caused by Methotrexate in a rat model

Abstract Methotrexate (MTX) is an antineoplastic and anti-inflammatory agent which is used in serious diseases. Its use should be limited due to side effects such as nephrotoxicity and hepatotoxicity, especially during high doses in cancer treatment. Hypertension may accompany patients due to nephrotoxicity, which is shown as one of the most important side effects. Nebivolol (NBV), which is a beta blocker and used in the treatment of hypertension, also contributes to vasodilation in tissues by activating endothelial nitric oxide synthase (eNOS) enzyme. The purpose of this study is to research the effect of NBV on MTX-induced nephrotoxicity through the AKT1/Hif-1⍺/eNOS signaling pathway.The rats were randomly divided into three groups of eight each. Groups were control, MTX and MTX + NBV. A single dose of 20 mg/kg MTX was given intraperitoneally to the rats on the first day of the study and 10 mg/kg NBV was given orally to the treatment group for seven days.At the end of the study, rats' blood and kidney tissues were taken for histopathological, immunohistochemical and biochemical examinations. Total antioxidant status levels were increased and total oxidant status levels were decreased significantly in MTX + NBV group compared with MTX group. Although creatinine levels increased in the MTX group compared to the control, while decreased in the MTX + NBV group. MTX administration was significantly decreased the expression levels of AKT1, eNOS and Hif1α compared to control group and NBV treatment increased these values compared to MTX group.In conclusion, NBV treatment ameliorated the MTX induced nephrotoxicity via AKT1/Hif-1⍺/eNOS signaling pathway.