Dagher Doha M, Zaghloul Marwa S, Suddek Ghada M
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura National University, Gamasa, Egypt.
J Biochem Mol Toxicol. 2025 Apr;39(4):e70257. doi: 10.1002/jbt.70257.
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.
镉是一种广泛分布于环境中的重金属，对人类健康构成严重危害。达格列净（DAPA）是一种钠-葡萄糖协同转运蛋白2（SGLT-2）抑制剂，具有抗氧化、抗凋亡和抗炎特性。我们的数据评估了DAPA对镉引发的大鼠肾脏和睾丸损伤的影响及其潜在机制。通过灌胃给予大鼠镉（30mg/kg）和DAPA（5mg/kg和10mg/kg），持续21天。DAPA减轻了镉引发的肾脏和睾丸损伤，表现为血清肌酐、尿素氮和尿总蛋白浓度降低，同时肌酐清除率、尿肌酐和血清睾酮升高。此外，它减少了镉诱导的肾脏和睾丸组织病理学改变。DAPA通过显著提高p-AMPK/总AMPK、降低p-mTOR/总mTOR比值以及降低p62和LC3蛋白水平，刺激了受损的自噬通量。此外，DAPA显著降低了丙二醛含量，提高了谷胱甘肽水平和超氧化物歧化酶活性。此外，它增强了细胞保护性的Nrf2/HO-1信号通路。此外，它通过降低caspase-3表达减轻了肾脏和睾丸的凋亡细胞死亡。结论：DAPA促进自噬事件、对抗氧化应激和凋亡，从而减轻镉诱导的肾脏和睾丸损伤。这是通过调节AMPK/mTOR和增强Nrf2/HO-1通路实现的。
