Abstract

Exposure to environmental cadmium (Cd) or a high-fat diet (HFD) alone is a risk factor for chronic kidney disease (CKD), but their combined exposure is common yet understudied. Selenium (Se) is a micronutrient for organismal health with antioxidant and detoxifying properties. This study aimed to investigate whether dietary Se protects against nephrotoxicity induced by co-exposure to Cd and HFD (HFD + Cd) and to explore potential mechanisms. Male mice were fed a normal diet or an HFD (60% fat) with or without Cd (3.0 mg/kg diet) and/or Se supplementation (1.5 mg/kg diet) for 24 weeks. HFD + Cd significantly worsened renal histopathology, biochemical parameters, and injury markers. Mechanistic experiments revealed that HFD + Cd markedly disrupted renal mineral homeostasis (particularly of Cd, zinc, iron, copper, and manganese) and selenoprotein expression. HFD and/or Cd exposure influenced reduced glutathione's levels and its turnover by altering the expression of related biosynthetic and metabolic enzymes. HFD + Cd was associated with features of ferroptosis, consistent with iron dyshomeostasis and lipid peroxidation. Moreover, HFD + Cd activated the EIF2A and IRE1A branches of the unfolded protein response and the JNK/MAPK pathway, and was associated with increased apoptosis markers, including BAX/BCL2 ratio. Parallel changes in these markers raise the possibility that IRE1A may selectively activate JNK and downstream apoptosis signaling. Dietary Se supplementation mitigated these pathological changes and attenuated the pathways associated with ferroptosis and the inferred IRE1A/JNK-apoptosis axis. These findings suggest that dietary Se protects against Cd and HFD co-exposure-induced nephrotoxicity, pointing to a potential nutritional strategy for CKD prevention in populations co-exposed to Cd and HFD.