The protective role of zinc in hyperglycemia-induced kidney injury: molecular modulation of ferroptosis, apoptosis, and fibrosis

Nilüfer Akgün Ünal; Gamze Altun; Serpil Çilingiroğlu Anlı

The protective role of zinc in hyperglycemia-induced kidney injury: molecular modulation of ferroptosis, apoptosis, and fibrosis

Abstract

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<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.

Keywords

References

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Details

Primary Language

English

Subjects

Clinical Nutrition

Journal Section

Research Article

Authors

Nilüfer Akgün Ünal ^*
0000-0001-7750-482X
Türkiye

Gamze Altun
0000-0003-3959-9893
Türkiye

Serpil Çilingiroğlu Anlı
0000-0003-1966-7609
Türkiye

Publication Date

August 15, 2026

Submission Date

June 12, 2026

Acceptance Date

July 20, 2026

Published in Issue

Year 2026 Volume: 7 Number: 4

IZ

https://izlik.org/JA25JP75CN

Cite

RIS / Bibtex

APA

Akgün Ünal, N., Altun, G., & Çilingiroğlu Anlı, S. (2026). The protective role of zinc in hyperglycemia-induced kidney injury: molecular modulation of ferroptosis, apoptosis, and fibrosis. Journal of Medicine and Palliative Care, 7(4), 783-790. https://izlik.org/JA25JP75CN

AMA

1.Akgün Ünal N, Altun G, Çilingiroğlu Anlı S. The protective role of zinc in hyperglycemia-induced kidney injury: molecular modulation of ferroptosis, apoptosis, and fibrosis. J Med Palliat Care / JOMPAC / jompac. 2026;7(4):783-790. https://izlik.org/JA25JP75CN

Chicago

Akgün Ünal, Nilüfer, Gamze Altun, and Serpil Çilingiroğlu Anlı. 2026. “The Protective Role of Zinc in Hyperglycemia-Induced Kidney Injury: Molecular Modulation of Ferroptosis, Apoptosis, and Fibrosis”. Journal of Medicine and Palliative Care 7 (4): 783-90. https://izlik.org/JA25JP75CN.

EndNote

Akgün Ünal N, Altun G, Çilingiroğlu Anlı S (August 1, 2026) The protective role of zinc in hyperglycemia-induced kidney injury: molecular modulation of ferroptosis, apoptosis, and fibrosis. Journal of Medicine and Palliative Care 7 4 783–790.

IEEE

[1]N. Akgün Ünal, G. Altun, and S. Çilingiroğlu Anlı, “The protective role of zinc in hyperglycemia-induced kidney injury: molecular modulation of ferroptosis, apoptosis, and fibrosis”, J Med Palliat Care / JOMPAC / jompac, vol. 7, no. 4, pp. 783–790, Aug. 2026, [Online]. Available: https://izlik.org/JA25JP75CN

ISNAD

Akgün Ünal, Nilüfer - Altun, Gamze - Çilingiroğlu Anlı, Serpil. “The Protective Role of Zinc in Hyperglycemia-Induced Kidney Injury: Molecular Modulation of Ferroptosis, Apoptosis, and Fibrosis”. Journal of Medicine and Palliative Care 7/4 (August 1, 2026): 783-790. https://izlik.org/JA25JP75CN.

JAMA

1.Akgün Ünal N, Altun G, Çilingiroğlu Anlı S. The protective role of zinc in hyperglycemia-induced kidney injury: molecular modulation of ferroptosis, apoptosis, and fibrosis. J Med Palliat Care / JOMPAC / jompac. 2026;7:783–790.

MLA

Akgün Ünal, Nilüfer, et al. “The Protective Role of Zinc in Hyperglycemia-Induced Kidney Injury: Molecular Modulation of Ferroptosis, Apoptosis, and Fibrosis”. Journal of Medicine and Palliative Care, vol. 7, no. 4, Aug. 2026, pp. 783-90, https://izlik.org/JA25JP75CN.

Vancouver

1.Nilüfer Akgün Ünal, Gamze Altun, Serpil Çilingiroğlu Anlı. The protective role of zinc in hyperglycemia-induced kidney injury: molecular modulation of ferroptosis, apoptosis, and fibrosis. J Med Palliat Care / JOMPAC / jompac [Internet]. 2026 Aug. 1;7(4):783-90. Available from: https://izlik.org/JA25JP75CN