Nilüfer AKGÜN ÜNAL, Gamze ALTUN, Serpil ÇİLİNGİROĞLU ANLI
Journal of Medicine and Palliative Care - 2026;7(4):783-790
Aims: This study aimed to examine the molecular, immunohistochemical, and histopathological impacts of zinc (ZnSO?) 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-ZnSO?), type 2 diabetes mellitus (T2DM), and T2DM supplemented with zinc (T2DM-ZnSO?). Groups of diabetic subjects received 5 mg/kg/day ZnSO? intraperitoneally for a period of 4 weeks. The metallothionein-1a (MT-1a), transforming growth factor-beta 1 (TGF-beta1), 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-ZnSO? group maximized MT-1a gene expression, indicating enhanced cellular antioxidant defense, and significantly reduced TGF-beta1 and VEGF-A mRNA levels associated with tissue fibrosis and pathological angiogenesis (p<0.05). Immunohistochemical analysis showed that zinc decreased the levels of the classical apoptosis marker Caspase-3 and FTH1 accumulation, indicative of ferroptotic stress, whereas it increased the expression of the antioxidant enzyme GPX4. Despite the presence of strong cellular rescue signals at the genetic and protein levels, four weeks of zinc treatment was not yet sufficient to histologically reverse the existing tubulointerstitial collagen deposition and tubular degeneration in the aged diabetic kidney. Conclusion: Zinc supplementation generates a highly effective molecular protective barrier in the aged diabetic kidney by inhibiting oxidative stress, ferroptotic/apoptotic cell death, and profibrotic gene cascades. For cellular-level repair to translate into established structural tissue healing, longer treatment windows are likely required.
