Abstract
Acute kidney injury (AKI) is a serious complication of methotrexate (MTX). This study explored the protective effect of the isoflavone formononetin (FN) against MTX nephrotoxicity with an emphasis on oxidative stress, inflammation, and nuclear factor (erythroid-derived 2)-like 2/heme oxygenase 1 (Nrf2/HO-1) signaling. Rats received FN (10, 20, and 40 mg/kg) for 10 days and a single dose of MTX on day 7. MTX induced kidney injury was characterized by increased serum creatinine and urea, kidney injury molecule-1 (Kim-1), and several histological alterations. FN ameliorated kidney function and inhibited the renal tissue injury induced by MTX. Reactive oxygen species (ROS), lipid peroxidation (LPO), nitric oxide, and 8-Oxo-2′-deoxyguanosine were increased, whereas antioxidant defenses were diminished in the kidney of MTX-administered rats. In addition, MTX upregulated renal iNOS, COX-2, TNF-α, IL-1β, Bax, caspase-9, and caspase-3, and decreased Bcl-2, Nrf2, and HO-1. FN suppressed oxidative stress, LPO, DNA damage, iNOS, COX-2, proinflammatory cytokines, and apoptosis, and boosted Bcl-2, antioxidants, and Nrf2/HO-1 signaling in MTX-administered rats. In conclusion, FN prevents MTX-induced AKI by activating Nrf2/HO-1 signaling and attenuates oxidative damage and inflammation. Thus, FN may represent an effective adjuvant that can prevent MTX nephrotoxicity, pending further mechanistic studies.
Highlights
Methotrexate (MTX), a folic acid antagonist, is a potent chemotherapeutic agent used in the treatment of malignancies and inflammatory diseases [1]
We investigated the protective effect of FN against Acute kidney injury (AKI) in MTX-administered rats, pointing to its ability to suppress oxidative stress and inflammation, and the role of Nrf2 signaling
Serum was prepared from the blood samples, and the kidneys were washed in cold phosphate buffered saline (PBS)
Summary
Methotrexate (MTX), a folic acid antagonist, is a potent chemotherapeutic agent used in the treatment of malignancies and inflammatory diseases [1]. The mechanism of MTX nephrotoxicity is not fully understood, it has been reported to involve excess production of reactive oxygen species (ROS), inflammation, mitochondrial dysfunction, DNA damage, and caspase activation, eventually culminating in renal dysfunction [4,6,7,8]. One of the untoward effects of MTX is its ability to promote ROS production, leading to inflammation and cell death. Given the role of ROS and oxidative stress in the development of MTX nephrotoxicity, the induction of antioxidant and cytoprotective enzymes is critical. We investigated the protective effect of FN against AKI in MTX-administered rats, pointing to its ability to suppress oxidative stress and inflammation, and the role of Nrf signaling
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