#2344 Empagliflozin attenuates renal fibrosis through the DsbA-L-CAS-STING pathway in unilateral ureteral obstruction model

Abstract Background and Aims Chronic kidney disease (CKD) is associated with an increase in morbidity and mortality. Renal fibrosis is a common pathway leading to the progression of CKD. Recent studies have reported an improvement of CKD with use of sodium glucose cotransport 2 inhibitors (SGLT2i) in both patients with DM and those without it. However, the mechanism of SGLT2is effect upon CKD has not been elucidated. In current study, we examined the effect of SGLT2i on renal fibrosis in rats caused by unilateral ureteral obstruction (UUO). Methods Male Sprague Dawley rats (9-10 weeks, weighing 320-360 g) were randomly assigned to two groups (n=8 each). One group received empagliflozin after UUO induction while the other group was left untreated. Kidneys were harvested two weeks after UUO. We evaluated the mitochondrial damage pathway presumed to contribute to the inflammation. Results UUO has resulted in marked renal fibrosis and triggered the activation of the cGAS-STING pathway. Kidneys in the empagliflozin treated group exhibited reduced size compare to the untreated group. Creatinine levels were lower in the empagliflozin group. Empagliflozin has been shown to attenuate renal fibrosis in histopathology. Western blot analysis revealed increased expression of disulfide-bond A oxidoreductase-like proteins (DsbA-L) was decreased cGAS-STING-NFκB in the empagliflozin group compared to the non-empagliflozin treated group (Fig. 1). Conclusion SGLT2i mitigated the progression of renal damage and fibrosis. This reno-protective effect is associated with increased DsbA-L and decreased of cGAS and STING pathway. These findings suggest that SGLT2i may alleviate mitochondrial damage in the UUO model. In addition, SGLT2i could be a promising medication to treat various forms of CKD.