Sotagliflozin prevents acute kidney injury by suppressing oxidative stress, inflammation, and apoptosis in renal ischemia/reperfusion rat model

Abstract

Introduction and aim. Acute kidney injury (AKI) is a life-threatening condition with limited effective pharmacological options. Although sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown renal protective effects, the potential role of the dual SGLT1/2 inhibitor sotagliflozin in ischemia/reperfusion injury (IRI) has not been previously investigated. We aimed to evaluate its nephroprotective properties in a rat model of renal IRI. Material and methods. Twenty-four male Sprague-Dawley rats were randomized into four groups (sham, control, dimethyl sulfoxide [DMSO], sotagliflozin). Renal IRI was induced by 40 min ischemia followed by 2 h reperfusion. Rats received either DMSO or sotagliflozin (10 mg/kg, intraperitoneally) 24 h and 1 h before surgery. Kidney function (urea, creatinine, neutrophil gelatinase-associated lipocalin [NGAL]), oxidative stress (8-iso-prostaglandin F2α [8-iso-PGF2α]), inflammation (tumor necrosis factor-alpha [TNF-α]), apoptosis (caspase-3), and histopathology were assessed. Results. In the control group, serum urea (106.5±2.9 mg/dL), creatinine (1.52±0.09 mg/dL), and NGAL (64.5±3.6 ng/mL) were significantly higher than in the sham group (32.6±5.3, 0.89±0.06, 49.5±3.8, respectively; p<0.0001). Tissue 8-iso-PGF2α (63.8±5.9 pg/mL), TNF-α (186±7 pg/mL), and caspase 3 (120.3±6.5 pmol/L) were also elevated vs. sham (35.6±3.6, 137±7, 92.3±4.9; p<0.0001). Sotagliflozin pretreatment reduced urea (53.8±2.8 mg/dL), creatinine (1.04±0.07 mg/dL), NGAL (49.6±6.4 ng/mL), 8-iso-PGF2α (41.3±3.9 pg/mL), TNF-α (140±6.6 pg/mL), and caspase 3 (89.7±2.4 pmol/L; all p<0.0001 vs. control). Histological injury scores improved from 4.0 in control to 1.0 in the sotagliflozin group (p<0.05). Conclusion. Sotagliflozin significantly improved renal function and histopathological damage in rats with renal IRI by attenuating oxidative stress, inflammation, and apoptosis. These findings support its potential as a candidate for further investigation in the prevention of AKI.