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

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.