PTEN对NLRP3炎症小体活性的调控在糖尿病肾病肾小管上皮细胞焦亡中的作用及机制研究

糖尿病肾病（DN）是导致终末期肾病的主要原因之一，其发病机制尚未阐明。目前认为与炎症反应密切相关的细胞焦亡可能促进了DN的肾损伤，但具体机制不清楚。研究显示第10号染色体缺失的磷酸酶和张力蛋白同源基因（PTEN）与炎症反应的发生具有相关性，且PTEN调控的下游蛋白FAK对炎症小体蛋白活化可能具有促进作用。我们研究发现，DN肾组织PTEN表达减少，而炎症及焦亡相关蛋白表达增多，推测PTEN对炎症小体活化及焦亡发生可能具有调节作用，但具体机制未见报道。本研究拟以糖尿病肾病患者、糖尿病小鼠和高糖培养的肾小管上皮细胞为研究对象，采用基因过表达、敲低及抑制等实验，探讨PTEN对NLRP3炎症小体主要成分ASC的磷酸化、寡聚化过程的调控，以及对GSDMD转录活性和蛋白活化的影响，为进一步阐明DN发病机制、寻找有效治疗靶点提供实验依据。

Diabetic nephropathy (DN) is one of the main causes of end-stage renal disease, which has complicated pathogenesis and not been elucidated. Pyroptosis, at present, is thought to be closely related to the inflammatory response, and it may contribute to kidney injury in DN with an unclearly regulation mode. Studies show that phosphatase and tensin homolog deleted on chromosome 10 (PTEN) are related to the inflammatory response, and its downstream protein focal adhesion kinase (FAK) may promote the activation of inflammasome protein. Our study found that the expression of PTEN was reduced while inflammatory and pyroptosis-related proteins were increased in renal tissue of DN, which speculated that PTEN may regulate the activation of inflammasome and the occurrence of pyroptosis. However the specific mechanism has not been reported. Taking diabetic nephropathy patients, diabetic mice and renal tubular epithelial cells under high-glucose cultivation as the research objects, we intend to over-express or knock-down of PTEN gene or apply inhibitors to explore the effects of PTEN on phosphorylation and oligomerization of apoptosis associated speck-like protein containing a CARD (ASC), the main component of NLRP3 inflammasome, and on Gasdermin-D (GSDMD) transcriptional activity and protein activation. This may provide experimental evidence for further elucidation of the pathogenesis of DN and the search for effective therapeutic targets.