A13742 SGLT2 inhibitor prevents renal fibrosis after renal ischemia/reperfusion injury in mice

Abstract

Objectives: Recent clinical studies have indicated that treatment with a SGLT2 inhibitor improves renal outcome in patients with type 2 diabetes who have high risks of cardiovascular events; however, its responsible mechanism has been undetermined. In the present study, we examined the effects of a SGLT2 inhibitor, luseogliflozin (LUSEO), on renal fibrosis after acute kidney injury in mice. Methods: LUSEO (30 mg/kg/day, p.o.) was administered at 6 hours after renal ischemia/reperfusion (I/R), and daily treatment was continued until for 7 days. Results: LUSEO did not affect the I/R-induced acute increases in plasma BUN levels, as well as tubular damage and autophagy. On the other hand, LUSEO significantly suppressed the development of renal fibrosis at week 4 after I/R. In addition, LUSEO prevented congestion/hemorrhage of peritubular capillaries, attenuated the loss of renal CD31-positive cell number and pericyte activation after I/R injury. These effects were accompanied with the increase in peritibular endothelial growth factor (VEGF)A mRNA expression level. Furthermore, treatment with sunitinib, abolished a VEGF inhibitor, these renoprotective effects of LUSEO. Conclusion: These data indicate that SGLT2 inhibitor attenuates the I/R-induced endothelial rarefaction and associated renal fibrosis through VEGF-dependent pathway.