抗肾间质纤维化新药—氟非尼酮抑制NLRP3炎性小体活化的分子机制研究

Renal interstitial fibrosis is the common pathway of all types of chronic kidney diseases. NLRP3 inflammasome-mediated immune response plays critical roles in promoting renal interstitial fibrosis. Recent studies reveal that mitochondrial damage during inflammation is key event that triggers the activation of NLRP3 inflammasome. However, the underlying mechanisms by which inflammation results in mitochondrial damage still remains elusive. Fluorofenidone is a novel anti-fibrotic compound designed by our group. Our previous works established that fluorofenidone prevents renal interstitial fibrosis by selective inhibition of the NLRP3 inflammasome activation. During the course of the studying the underlying mechanisms using metabolomic approach, we discovered that fluorofenidone prevents the loss of malonic acid during inflammation. Recent study shows that the loss of malonic acid induces mitochondrial damage during ischemia/reperfusion injury（Nature. 2014, 515: 431-5）. In the light of this finding, we hypothesize that fluorofenidone might reduce mitochondrial damage and NLRP3 inflammasome activation through preventing the loss of malonic acid during inflammation. This project might not only reveal the concrete pharmacological mechanisms by which fluorofenidone inhibits renal interstitial fibrosis, but also provide novel insights into how inflammatory insults induce mitochondrial damage and the activation of NLRP3 inflammasome.

肾间质纤维化是慢性肾脏疾病进行性发展的共同通路和主要病理基础，NLRP3炎性小体介导的炎症反应在肾间质纤维化中起重要促进作用。近年研究发现，线粒体损伤是NLRP3炎性小体活化的关键环节，但线粒体损伤在炎症反应中的发生机制至今仍不甚清楚。氟非尼酮是本课题组自主研发的新型抗纤维化药物。我们的前期工作表明：氟非尼酮能选择性的抑制NLRP3炎性小体的活化，从而发挥其抗肾间质纤维化作用。近期我们利用代谢组学方法观察到：氟非尼酮在炎症反应中能防止丙二酸丢失。结合新近研究发现——缺血再灌注过程中丙二酸丢失能造成线粒体损伤（Nature. 2014, 515: 431-5），我们推测：氟非尼酮在炎症反应中可能通过防止丙二酸的丢失、减轻线粒体损伤，进而抑制NLRP3炎性小体活化。本课题的开展不仅能进一步阐明氟非尼酮抗肾间质纤维化的作用机制，而且还可能揭示炎症反应中线粒体损伤和NLRP3炎性小体活化的新机制。

氟非尼酮（Fluorofenidone, AKF-PD）是一种吡啶酮类小分子化合物，其具有良好的抗肾纤维化效果。我们之前的研究证明氟非尼酮在UUO模型中可以通过抑制NLRP3炎性体活化发挥抗肾纤维化作用，但是具体作用机制尚不明确。本研究我们探讨了氟非尼酮是否通过丙二酸来抑制NLRP3炎性体活化。结果表明氟非尼酮可通过增加巨噬细胞中丙二酸丰度，减少线粒体损伤，抑制NLRP3炎性体活化，继而发挥抗肾纤维化作用。进一步的实验发现氟非尼酮能够增加线粒体能量代谢，增强线粒体生物生发，减少线粒体相关的氧化应激和凋亡。此外，我们还发现丙二酸可以通过拮抗琥珀酸与GPR91受体结合，发挥抗炎抗肾纤维化作用。本研究的开展不仅为氟非尼酮治疗肾纤维化提供了新的理论基础，还为丙二酸治疗肾纤维化提供了有力的证据。