Empagliflozin mitigates doxorubicin-induced nephrotoxicity by modulating sirtuin 1, nuclear factor-κB/tumor necrosis factor-α, and cleaved caspase-3 pathways without compromising its cytotoxic efficacy

Doxorubicin (DOX), an anthracycline antibiotic, is a first-line chemotherapy drug for managing various tumors. Its hazards, particularly nephrotoxicity, complicate its clinical application. Empagliflozin (EMPA), an antidiabetic drug inhibiting sodium-glucose cotransporter 2, exhibits multiple benefits in different illnesses based on its ability to mitigate oxidative injury, inflammation, and apoptosis. Therefore, this work was conducted to evaluate EMPA's therapeutic efficacy in abrogating DOX-elicited renal impairment and to elucidate the underlying mechanisms mediating this proposed ameliorative effect. Thirty-four male Wistar rats randomly divided into control, EMPA (10 mg/kg/d, intragastric (i.g.), DOX (20 mg/kg, single intraperitoneal injection on day 10), and DOX + EMPA (10 mg/kg/d of EMPA, i.g. administration for 12 days and 20 mg/kg, single intraperitoneal injection of DOX on day 10) were involved. In vitro cytotoxicity assay was also performed using KMH2, MG63, and MCF7 cancer cell lines. Counteraction of DOX-impaired renal function by EMPA was proved by a decline in levels of serum urea, creatinine, and cystatin C levels, as well as preserved renal architecture. EMPA mitigated oxidative stress in renal tissues, as presented by a reduction in malondialdehyde and an increase in both reduced glutathione and superoxide dismutase. Moreover, EMPA alleviated DOX-induced downregulation of sirtuin 1 and upregulation of nuclear factor-κB, tumor necrosis factor-α, and cleaved caspase-3. Additionally, the cytotoxic activity of DOX in KMH2 and MG63 cancer cell lines was significantly (P < .05) promoted by EMPA. Collectively, antioxidant, anti-inflammatory, and antiapoptotic influences contributed to the preservative potential of EMPA against DOX-induced kidney toxicity. Moreover, EMPA enhanced the DOX cytotoxic impact in different cancer cell lines. SIGNIFICANCE STATEMENT: This study demonstrates that empagliflozin attenuates doxorubicin (DOX)-induced renal impairment in rats and promotes DOX's cytotoxic effects via its antioxidant and anti-inflammatory potentials. These preclinical findings highlight empagliflozin as a hopeful therapeutic tool to preserve the kidney during DOX treatment.