The protective role of zinc in hyperglycemia-induced kidney injury: molecular modulation of ferroptosis, apoptosis, and fibrosis
Aims: This study aimed to examine the molecular, immunohistochemical, and histopathological impacts of zinc (ZnSO₄) supplementation on apoptosis, ferroptosis, and fibrosis pathways in the kidney tissue of aged female rats with type 2 diabetes, induced by a high-fat diet and streptozotocin (STZ). Methods: Female rats aged 18 months were allocated into four groups: Normoglycemic (NRM), normoglycemic supplemented with zinc (NRM-ZnSO₄), type 2 diabetes mellitus (T2DM), and T2DM supplemented with zinc (T2DM-ZnSO₄). Groups of diabetic subjects received 5 mg/kg/day ZnSO₄ intraperitoneally for a period of 4 weeks. The metallothionein-1a (MT-1a), transforming growth factor-beta 1 (TGF-β1), and vascular endothelial growth factor-A (VEGF-A) gene expressions were assessed by quantitative reverse transcription polymerase chain reaction (RT-qPCR). Protein levels of cysteine-aspartic acid protease 3 (Caspase-3), glutathione peroxidase 4 (GPX4), ferritin heavy chain 1 (FTH1), and VEGF were evaluated by immunohistochemistry; cellular damage and collagen deposition were determined by periodic acid-Schiff (PAS) and Masson trichrome staining. Results: Zinc supplementation in the T2DM-ZnSO₄ group maximized MT-1a gene expression, indicating enhanced cellular antioxidant defense, and significantly reduced TGF-β1 and VEGF-A mRNA levels associated with tissue fibrosis and pathological angiogenesis (p