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. 2025 Apr;39(4):e70257.
doi: 10.1002/jbt.70257.

Modulation of AMPK/mTOR Autophagic Pathway Using Dapagliflozin Protects Against Cadmium-Induced Testicular and Renal Injury in Rats

Doha M Dagher  1 , Marwa S Zaghloul  1   2 , Ghada M Suddek  1
Affiliations

Modulation of AMPK/mTOR Autophagic Pathway Using Dapagliflozin Protects Against Cadmium-Induced Testicular and Renal Injury in Rats

Doha M Dagher et al. J Biochem Mol Toxicol. 2025 Apr.

Abstract

Cadmium is a widely distributed heavy metal found in the environment that poses serious hazards to human health. Dapagliflozin (DAPA), a sodium-glucose co-transporter 2 (SGLT-2) inhibitor, exhibited antioxidant, antiapoptotic, and anti-inflammatory properties. Our data assessed the effect of DAPA against Cd-triggered renal and testicular impairment in rats, as well as the underlying mechanisms. Cd (30 mg/kg) and DAPA (5 and 10 mg/kg) were administrated by oral gavage to rats and continued for 21 days. DAPA attenuated Cd-triggered renal and testicular injury as shown by diminishing serum creatinine, BUN, and urinary total protein concentration in addition to increasing creatinine clearance, urinary creatinine, and serum testosterone. Moreover, it diminished renal and testicular histopathological alterations induced by Cd. DAPA stimulated the impaired autophagy flux as seen by significantly elevating the p-AMPK/total AMPK, decreasing p-mTOR/total mTOR ratios, and diminishing p62 & LC3 protein levels. Additionally, DAPA significantly lowered MDA content, increased GSH level and SOD activity. Moreover, it augmented the cytoprotective Nrf2/HO-1 signaling pathway. Furthermore, it attenuated renal and testicular apoptotic cell death via decreasing caspase-3 expression. Conclusion: Boosting autophagic events and combating oxidative stress and apoptosis by DAPA were engaged in alleviating Cd-induced renal and testicular impairment. This was accomplished by modulating the AMPK/mTOR and enhancing the Nrf2/HO-1 pathways.

Keywords: AMPK; HO‐1; Nrf2; autophagy; cadmium; dapagliflozin.

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References

    1. L. Patrick, “Toxic Metals and Antioxidants: Part II. The Role of Antioxidants in Arsenic and Cadmium Toxicity,” Alternative Medicine Review: A Journal of Clinical Therapeutic 8, no. 2 (2003): 106–128.
    1. J. J. V. Branca, G. Morucci, M. Maresca, et al., “Selenium and Zinc: Two Key Players Against Cadmium‐Induced Neuronal Toxicity,” Toxicology In Vitro 48 (2018): 159–169.
    1. N. Tarasub and K. Narula, “Effects of Curcumin on Cadmium‐Induced Hepatotoxicity in Rats,” Thai Journal of Toxicology 23, no. 2 (2008): 100.
    1. V. Andrade, M. Aschner, and A. Marreilha Dos Santos, “Neurotoxicity of Metal Mixtures,” Neurotoxicity of metals 18 (2017): 227–265.
    1. E. C. Panel, “Cadmium in Food‐Scientific Opinion of the Panel on Contaminants in the Food Chain,” EFSA Journal 980 (2009): 1–139.

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