Resveratrol regulates nickel oxide-induced kidney damage by targeting the PERK/ATF-6/IRE1 and Nrf2/HO1 pathways

Abstract Nickel oxide (NiO) is one of the most toxic heavy metals and poses a danger to human and animal health by causing serious kidney damage. Resveratrol (RES) is a flavonoid with antioxidant and anti-inflammatory properties, abundant in grapes and fruits. The current study is a first to investigate how RES affects oxidative stress, apoptosis, endoplasmic reticulum (ER) stress, inflammation, and histopathology against NiO-induced nephrotoxicity in rats using molecular, histological, immunohistochemical, and biochemical methods. The study used 24 Sprague–Dawley rats, randomly distributed into 4 groups of 6 rats each. The groups were designated as control, RES (10 mg/kg), NiO (10 mg/kg), and RES plus NiO. For 28 days, the prescribed doses of NiO and RES were given to the rats through gavage. After receiving NiO for 28 days, rats showed elevated levels of blood urea, creatinine, and uric acid. It has led to a rise in malondialdehyde (MDA) levels, an indicator of oxidative stress, and a decline in the transcription factor nuclear factor erythroid 2–related factor 2 (Nrf2) and antioxidant enzymes (HO-1, SOD, CAT, GPx, and GST). NiO application also increased the levels of IL-1β, TNF-α, 8-OHdG, and caspase-3 and the expression of endoplasmic reticulum (ER) stress markers such as heat shock proteins (HSP70, HSP90), GRP78, PERK, ATF6, ATF4, IRE1, XBP1, and CHOP, leading to histopathological changes in kidney tissues. RES administration significantly improved histological appearance by reducing impaired renal biochemistry, increased oxidative stress, inflammation, and ER stress. These results demonstrated that RES reduced NiO-induced nephrotoxicity. Graphical Abstract