Zinc Deficiency Aggravates High-Fat Diet-Induced Renal Injury by Regulating Oxidative Stress and Inflammation via the Nrf2/HO-1 Pathway.

Obesity-related kidney disease (ORG) is associated with oxidative stress and inflammation. Zinc plays a crucial role in antioxidative defense, but its deficiency may exacerbate renal injury. The role of Zn deficiency in obesity-induced oxidative stress remains unclear. Male C57BL/6J mice were divided into four groups: ND/NZ (normal diet, normal Zn), ND/LZ (normal diet, low Zn), HFD/NZ (high-fat diet, normal Zn), and HFD/LZ (high-fat diet, low Zn) groups. After 24 weeks, renal function, histopathology, oxidative stress, and inflammatory markers were analyzed. The levels of ROS and key proteins in the Nrf2/HO-1 and PI3K/Akt pathways were assessed via Western blotting and immunofluorescence. An in vitro MPC5 podocyte model was used to examine the effects of Zn under palmitic acid stimulation, with siRNA-mediated Nrf2 knockdown. Zn deficiency exacerbated renal dysfunction, fibrosis, and inflammation in obese mice; increased ROS levels; suppressed Nrf2 signaling; and activated PI3K/Akt. In vitro, Zn supplementation reduced ROS levels and restored Nrf2 nuclear translocation, whereas Nrf2 knockdown aggravated oxidative stress. Zn deficiency promotes obesity-induced renal injury by increasing oxidative stress and inflammation through Nrf2 inhibition and PI3K/Akt activation.