醛固酮通过小窝蛋白1介导NLRP3炎症小体活化促进肝星状细胞焦亡

Previous investigations showed that Aldosterone（Aldo） activated hepatic stellate cells (HSCs) and induced liver fibrosis. Caveolae is a cup shape structure on the surface of the cell membrane. Caveolin-1 (cav-1) is the main protein of caveolae, which can bind to the receptor of MR, the receptor of Aldo, and regulates oxidative stress and inflammation in its non-genomic pathway. The latest researches showed that NLRP3 inflammasome induced liver fibrosis by regulating pyroptosis. It is not reported whether Aldo induce fibrosis in its non-genomic pathway by cav-1 mediated activation of NLRP3 inflammasome. Our previous study found that Aldo activated NLRP3 inflammasome in a cav-1 mediated non-genomic pathway. Base on this, we make an assumption that Aldo activates NLRP3 inflammasome through cav-1, and induces pyroptosis of HSC; pyroptosis shows positive feedback to activate NLRP3 inflammasome, further promoting inflammation and liver fibrosis. This study makes caveolae as a micro-environment, and potassium as a link to cycle inflammation and pyroptosis. The mechanisms of aldosterone-induced activation of HSC through NLRP3 inflammasome and pyroptosis are explored in vitro and in vivo. This study provides new insights for aldosterone regulating liver fibrosis.

既往研究表明，醛固酮（Aldo）可活化肝星状细胞（HSC），促进肝纤维化。小窝是细胞膜表面的凹陷结构，内含小窝蛋白1（cav-1）可与Aldo受体MR结合，发挥非基因组效应，调节氧化应激与炎症反应。最新研究表明，NLRP3炎症小体及其调控的细胞焦亡可促进肝纤维化形成。Aldo经cav-1介导的非基因组效应能否激活NLRP3炎症小体进而促进纤维化？未见相关报道。我们的前期研究发现：Aldo可通过cav-1介导的非基因组效应促进 NLRP3炎症小体活化。因此我们设想：Aldo通过cav-1激活NLRP3炎症小体，促进HSC焦亡；HSC焦亡对NLRP3炎症小体活化形成正反馈，进一步促进炎症反应及肝纤维化形成。本研究以小窝结构作为微观环境，以钾离子作为纽带将炎症与焦亡连成一体，从体内、体外层面探讨醛固酮通过NLRP3炎症小体及焦亡活化肝星状细胞的机制。本研究为醛固酮调控纤维化的机制提供新思路。

肝星状细胞（HSC）活化是肝纤维化的重要环节。我们的研究发现，HSC表面的小窝结构中，小窝蛋白1（cav-1）可与醛固酮（Aldo）受体MR结合，发挥非基因组效应，调节下游氧化应激与炎症反应。我们进一步证明，Aldo经cav-1介导的非基因组效应激活NLRP3炎症小体促进HSC焦亡；HSC焦亡对NLRP3炎症小体活化形成正反馈，进一步促进炎症反应及肝纤维化形成。沃诺拉赞（Vonoprazan）作为钾离子通道抑制剂可抑制HSC的NLRP3炎性小体的激活，进而抑制HSC活化。本项目以小窝结构为微观环境，探索肝星状细胞中NLRP3炎症小体与焦亡的关联，为醛固酮的促肝纤维化作用寻找研究切入点及治疗靶点。螺内酯作为醛固酮的受体拮抗剂，寻找其拮抗肝纤维化的依据。同时挖掘新型制酸药沃诺拉赞（Vonoprazan）作为钾离子通道抑制剂，其对肝纤维化的潜在治疗作用。