Sodium-glucose co-transporter 2 (SGLT-2) inhibitors ameliorate renal ischemia-reperfusion injury (IRI) by modulating autophagic processes.

Abstract

Renal ischemia-reperfusion injury (IRI) is a common clinical condition that currently lacks effective treatment options. Inhibitors targeting the sodium-glucose co-transporter-2 (SGLT-2), recognized for their role in managing hyperglycemia, have demonstrated efficacy in enhancing the health outcomes for diabetic patients grappling with chronic kidney disease. Nevertheless, the precise impact of SGLT-2 inhibitors on renal ischemia-reperfusion injury (IRI) and the corresponding transcriptomic alterations remain to be elucidated. In our research, we developed a model of IRI using male C57BL/6 mice by clamping the unilateral renal artery and administering empagliflozin Transcriptomic alterations were analyzed using RNA sequencing (RNA-Seq), complemented by proteomic analysis to investigate the effects of empagliflozin. Histological assessments revealed increased renal inflammatory cell infiltration, widespread renal tubular injury, and elevated autophagosomes formation in the IRI group compared to controls. These pathological changes were significantly attenuated following empagliflozin treatment. Besides, renal function impairment can be alleviated in empagliflozin-treated group. RNA-Seq analysis identified lysosomal autophagy as a key biological process in IRI mice. Empagliflozin exerted a renoprotective effect by downregulating lysosome-associated membrane proteins, primarily LAMP1, LAMP2, and LAMP4 (CD68), through the PI3K-Akt, MAPK, and mTOR signaling pathways, thereby inhibiting autophagic processes. In conclusion, this study highlights enhanced inflammation and disrupted metabolism as hallmark transcriptomic signatures of renal. Furthermore, it demonstrates the renoprotective effects of empagliflozin in alleviating renal IRI by modulating autophagic processes.