Targeting oxidative stress, apoptosis, and autophagy by galangin mitigates cadmium-induced renal damage: Role of SIRT1/Nrf2 and AMPK/mTOR pathways

Galangin, a bioactive flavonoid with remarkable antioxidant and anti-apoptotic actions, has demonstrated promising amelioration of experimental hepatotoxicity, cardiomyopathy, and colitis. Yet, its impact on cadmium-induced renal injury has not been explored. Herein, we aimed at exploring the potential of galangin to attenuate cadmium-induced nephrotoxicity in rats, focusing on oxidative stress, apoptosis, and autophagy. Cadmium chloride (5 mg/kg/day) and galangin (15 mg/kg/day) were received by oral gavage and the kidney tissues were inspected using ELISA, biochemical measurements, histology, and immunohistochemistry. Galangin attenuated cadmium-induced renal damage by diminishing the histopathological alterations alongside KIM-1, BUN, and creatinine. At the molecular level, galangin attenuated the oxidative insult by significantly lowering the lipid peroxides and NOX-1 and augmenting GSH and GPx antioxidants. It also activated the cytoprotective SIRT1/Nrf2/HO-1 pathway by significantly upregulating the protein expression of SIRT1, Nrf2, and HO-1. Consistently, galangin suppressed renal apoptotic cell death by significantly lowering the protein expression of Bax and cytochrome C and activity of caspase-3 alongside upregulating the protein expression of the anti-apoptotic Bcl-2. Additionally, galangin activated the impaired autophagy flux as seen by diminishing the accumulation of SQSTM1/p62 and increasing the protein expression of Beclin 1. Meanwhile, galangin stimulated the autophagy-linked AMPK/mTOR pathway by significantly increasing the p-AMPK/total AMPK and lowering p-mTOR/total mTOR ratios. Galangin mitigated cadmium-induced nephrotoxicity thanks to its promising antioxidant, anti-apoptotic, and pro-autophagic effects. In perspective, galangin stimulated the SIRT1/Nrf2/HO-1 and AMPK/mTOR pathways. Hence, it may act as a complementary tool for the management of cadmium-induced renal injury. •Galangin improved the kidney function markers and histopathologic alterations in rats.•Galangin curtailed oxidative perturbations and enhanced renal antioxidants defenses.•Galangin activated the cytoprotective SIRT1/Nrf2/HO-1 pathway•Galangin dampened renal pro-apoptotic markers (caspase-3 activity and Bax/Bcl-2 ratio)•Galangin activated the renal autophagy flux and AMPK/mTOR pathway.