Program

PO1-3-22

Treatment with the SGLT2 inhibitor luseogliflozin attenuated renal capillary injury and fibrosis by VEGF after renal ischemia/reperfusion injury in mice

[Speaker] Daisuke Nakano:1
[Co-author] Yifan Zhang:1, Akira Nishiyama:1
1:Department of Pharmacology, Kagawa University, Japan

[Introduction] Sodium-glucose cotransporter (SGLT) 2 inhibitors increase glucose excretion in the urine by inhibiting glucose reabsorption in proximal tubules. It has been reported that its use in clinical reduces the risks of clinically relevant renal events. However, the effects of SGLT2 inhibition on the severity of kidney injury or on the efficiency of repair after injury have not been examined. We investigated the effects of the SGLT2 inhibitor luseogliflozin on renal ischemia/reperfusion injury and subsequent development of renal fibrosis in mice.
[Methods] Luseogliflozin (30 mg/kg/day, p.o.) was administered at 6 hours after renal ischemia/reperfusion (I/R), and the treatment was continued daily until day 7.
[Results] Luseogliflozin did not affect decline of creatinine clearance or histopathological damage at day 1 or 3 after I/R. In contrast, luseogliflozin significantly suppressed the development of renal fibrosis at day 7 and week 4 after I/R. Additionally, luseogliflozin prevented peritubular capillary congestion/hemorrhage, attenuated renal CD31-positive cell loss, and suppressed renal hypoxia after I/R injury. These changes were accompanied by an increase in renal VEGF-A mRNA levels. Furthermore, an in vivo glucose uptake analysis showed that luseogliflozin after I/R, but not after sham operation, halted glucose uptake in the proximal tubules, which was associated with the decrease in membranous GLUT2 level. Depleting glucose from cultured medium dramatically increased VEGF-A expression in proximal tubular cells. Finally, luseogliflozin failed to attenuate the renal I/R injury-induced fibrotic changes in the animals co-treated with sunitinib, a VEGF receptor inhibitor.
[Conclusion] These results indicate that luseogliflozin prevented endothelial rarefaction and the development of renal fibrosis after renal I/R injury through a VEGF-dependent pathway.


Advanced Search