Suramin inhibits activation of inflammasome and protects against progression of diabetic kidney disease in KK-AY mice

Background: Inflammasome is a protein complex that leads to production of IL-1β and IL-18 through activation of caspase-1, and danger-associated molecular patterns (DAMPs) trigger inflammasome activation via P2 receptors (P2Rs). We have shown that both serum and urinary IL-18 levels are elevated in patients with diabetic kidney disease (DKD). Mass spectrometry imaging has revealed that ATP, one of the major DAMPs, is increased in the glomeruli of diabetic mice. The aim of this study was to determine if suramin, a nonselective P2Rs antagonist, protects against DKD in KK-Ay mice. Methods: Four weeks-aged male C57BL/6 (B) mice and diabetic KK-Ay (K) mice (KK-Ay/TaJcl strain) were randomly assigned to four groups: B+vehicle (BV), B+suramin, K+vehicle (KV) and K+suramin (KS), 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 and proteins were quantified by quantitative PCR and western blot. The localization of P2Rs were examined by double staining. Results: Urinary albumin/creatinine ratio was elevated in KV (280.0 ± 29.3 mg/gCr, p<0.001) vs. BV (1.7 ± 0.3 mg/gCr), and significantly reduced in KS (160.6 ± 27.3 mg/gCr, p<0.01), whereas there were no significant differences in body weight or HbA1c between both diabetic groups. Glomerular size and glomerular mesangial matrix area were significantly increased in KV and reduced to 78% (p<0.001) and 66% (p<0.001) of KV levels by suramin treatment, respectively. Importantly, mRNA expression of P2X4R and P2X7R in both renal cortex and isolated glomeruli were significantly suppressed in KS compared with KV (p<0.05). P2X4R and P2X7R were mainly distributed in mesangial cells in the glomerulus of KK-Ay mice. Protein expression of NLRP3, a key component of inflammasome, was increased in KV vs. BV, and significantly suppressed in KS (p<0.05). The increase in IL-18 mRNA expression in KV was significantly suppressed in KS (p<0.01), and a similar trend was observed in IL-18 protein level in renal cortex. Conclusions: We found that suramin can improve features of DKD with type 2 diabetes and may be renoprotective via suppression of inflammasome activation. Suramin may be beneficial for the treatment of DKD.