Development of the new therapeutic strategy for diabetic nephropathy by modulation of inflammasome.

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K08635
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53040:Nephrology-related
• Research Institution: Okayama University
• Principal Investigator: Kenichi Shikata 岡山大学, 大学病院, 教授 (00243452)
• Co-Investigator(Kenkyū-buntansha): 宮本 聡 岡山大学, 大学病院, 助教 (60779429)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: 糖尿病性腎症 / インフラマソーム

Outline of Final Research Achievements

NLRP3 inflammasomes produce IL-18 upon being activated by various stimuli via the P2 receptors. The aim of this study is to clarify the role of inflammasome in the pathogenesis of diabetic kidney disease (DKD).Treatment with suramin, a nonselective antagonist of the P2 receptors, significantly suppressed the renal injuries in KK-Ay mice. Suramin also suppressed the upregulation of NLRP3 inflammasome-related genes and proteins in the renal cortex of KK-Ay mice. P2X4 and P2X7 receptors were significantly upregulated in the isolated glomeruli of KK-Ay mice and mainly distributed in the glomerular mesangial cells of KK-Ay mice. Suramin inhibited ATP-induced NLRP3 complex formation and the downstream expression of caspase-1 and IL-18 in MMCs. Furthermore, we analyzed the effects of ATP on mesangial cell using DNA microarray and found the gene cluster which changed by ATP stimulation. Conclusions: These results indicate that the NLRP3 inflammasome is involved in the pathogenesis of DKD.

Free Research Field

糖尿病学

Academic Significance and Societal Importance of the Research Achievements

我々は、これまで糖尿病性腎症の成因に炎症が関与することを報告してきた。腎症の成因における炎症の関与については、最近になって多くの報告が見られるようになった。本研究は、糖尿病性腎症の成因におけるインフラマソームの役割を明らかにするとともに、インフラマソームを制御することによって腎症の進展を抑制できることを示した。さらに、ATPによってメサンギウム細胞には縷言が誘導される遺伝子群を明らかにした。本研究は、世界的に先駆的な研究であり、今後の腎症の治療薬の開発につながるものである。