Abstract: TH-PO670

Inhibiting Inflammasome Activation with Suramin Protects against Progression of Diabetic Kidney Disease in KK-Ay Mice

Session Information

Category: Diabetes

  • 501 Diabetes Mellitus and Obesity: Basic - Experimental

Authors

  • Oda, Kaori, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
  • Miyamoto, Satoshi, Center for Innovative Clinical Medicine,Okayama University Hospital, Okayama, Japan
  • Kodera, Ryo, Center for Innovative Clinical Medicine,Okayama University Hospital, Okayama, Japan
  • Wada, Jun, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
  • Shikata, Kenichi, Center for Innovative Clinical Medicine,Okayama University Hospital, Okayama, Japan
Background

Recent reports have suggested that innate inflammation via inflammasome activation is involved in the pathogenesis of diabetic kidney disease (DKD). Inflammasome, a protein complex, is activated in various diseases, leading to production of IL-1β and IL-18 through activation of caspase-1. In addition, danger-associated molecular patterns (DAMPs) are the crucial triggers for inflammasome activation via its receptors including P2X and P2Y receptors. We have demonstrated that both serum and urinary IL-18 levels are elevated in patients with DKD (Nakamura A et al. Diabetes Care, 2005), and that ATP, one of the important DAMPs, is increased in the glomeruli of diabetic mice by mass spectrometry imaging (Miyamoto S et al. EBioMedicine, 2016). The aim of this study was to determine if suramin, a non-selective P2X and P2Y antagonist, protects against DKD in KK-Ay mice.

Methods

Four weeks-aged male nondiabetic C57BL/6 mice and diabetic KK-Ay mice (KK-Ay/TaJcl) were randomly assigned to four groups: C57BL/6+vehicle (Control), C57BL/6+suramin, KK-Ay+vehicle (KK-Ay), KK-Ay+suramin, n=6-12/group. Vehicle or suramin (1 mg/kgBW) were injected intraperitoneally once every two weeks over an 8-week period. Glomerular size and mesangial matrix area were assessed by morphometric analysis. Expression of inflammasome-related genes in renal cortex were examined by quantitative real-time PCR.

Results

Urinary albumin/creatinine ratio, elevated in KK-Ay (280.0 ± 29.3 mg/gCr, p<0.001) vs. Control (1.7 ± 0.3 mg/gCr) mice, was significantly reduced with suramin (160.6 ± 27.3 mg/gCr, p<0.01), whereas there were no significant differences in body weight or HbA1c between both diabetic groups. The increases in both glomerular size and glomerular mesangial matrix area in KK-Ay group, were significantly reduced with suramin (p<0.001). In addition, the increase in inflammasome-related gene expressions including IL-18, P2X4 and P2X7 in KK-Ay group were significantly suppressed with suramin (p<0.001).

Conclusion

Our results suggest that inflammasome is activated in the diabetic kidney and the inhibition of inflammasome with suramin protects against progression of DKD. Suramin may be beneficial for the treatment of DKD.

Funding

  • Commercial Support