Kidney Week

Abstract: TH-PO314

Treatment with the SGLT2 Inhibitor Luseogliflozin after Ischemia/Reperfusion Attenuated Renal Fibrosis through Reversing the Endothelial Rarefaction in Mice

Session Information

• AKI Basic: Oxidative Injury and Nephrotoxins
  November 02, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Acute Kidney Injury

• 001 AKI: Basic

Authors

• Nakano, Daisuke, Kagawa University, Kagawa, Japan

Daisuke Nakano,

• Nishiyama, Akira, Kagawa University, Kagawa, Japan

Akira Nishiyama,

Background

Sodium-glucose cotransporter (SGLT) 2 inhibitors increase glucose excretion in the urine by inhibiting glucose reabsorption in proximal tubules. However, the effects of SGLT2 inhibition on the severity of proximal tubular injury or on the efficiency of repair after injury have not been examined.

Methods

We investigated the effects of the SGLT2 inhibitor luseogliflozin on acute kidney injury and subsequent development of renal fibrosis in mice. Luseogliflozin (30 mg kg⁻¹ day ⁻¹, 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 blood urea nitrogen increases, histopathological damage, or autophagy induction 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, and attenuated renal CD31-positive cell loss after I/R injury. These changes were accompanied by an increase in renal VEGF-A mRNA levels. Furthermore, luseogliflozin failed to attenuate the renal I/R injury-induced fibrotic changes in the animals co-treated with sunitinib, a VEGF receptor inhibitor. Finally, low glucose concentration in the medium increased VEGF-A mRNA levels in cultured proximal tubular cells, and an in vivo glucose uptake analysis showed that luseogliflozin after I/R suppressed glucose uptake in the proximal tubules.

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.

Funding

• Commercial Support – Taisho-Toyama Pharma. Inc