基于HIF/JMJD1A/MALAT1信号通路探讨肾康丸干预糖尿病肾病内皮细胞损伤的机制研究

肾小球内皮细胞（RGEC）损伤是糖尿病肾病（DN）发生发展的重要机制，缺氧是RGEC损伤的重要环节。我们前期研究发现，缺氧可上调HIF-1α表达，增强RGEC炎性损伤，其并非通过NF-κB通路实现。进一步通过基因芯片筛选,发现lncRNA MALAT1在高糖刺激下RGEC中表达增高，HIF-1α可诱导增强MALAT1介导的炎症级联反应，此过程可能通过靶向调控组蛋白去甲基化酶JMJD1A而实现。据此我们提出假说：HIF-1α可激活JMJD1A，进而调控MALAT1表达，诱导发生RGEC炎症损伤。目前此方面研究未见报道。本项目拟通过利用JMJD1A敲除小鼠模型及基因沉默细胞模型，采用Co-IP、CHIP、Western-Blot、qRT-PCR等方法，探讨HIF/JMJD1A/MALAT1信号通路在RGEC损伤中的作用，以及肾康丸对该通路的影响，为研究中药治疗DN的机制和靶点提供科学证据。

Renal glomerular endothelial cell (RGEC) injury accelerates the progression of diabetic nephropathy (DN). Hypoxia is an important reason for RGEC injury. Our previous works found that hypoxia can upregulate HIF-1α expression and enhance RGEC inflammatory injury, which did not pass through the NF-κB signal pathway. Furthermore, previous gene microarray data demonstrated that the expression of lncRNA MALAT1 increased in RGEC stimulated by high glucose. During the process of MALAT1-mediated inflammatory cascade induced by HIF-1α, histone demethylase JMJD1A might be targeted to modulated by HIF-1α. Therefore, We hypothesize that HIF-1α activates JMJD1A, which regulates MALAT1 expression and induces RGEC inflammatory damage. There has no relative research reported in this field. We will adopt JMJD1A knockout mouse model and gene silencing cell model to study the role of HIF/JMJD1A/ MALAT1 signaling pathway in pathogenesis of DN by Co-IP, CHIP, Western-Blot and qRT-PCR. We will administrate Shen-Kang pill for DN mouse, which has good effect for improving DN in human, to demonstrate whether Shen-Kang pill alleviate RGEC injury via HIF / JMJD1A / MALAT1 signaling pathway. We expect that our research can provide scientific evidences to explain the treatment mechanism and target of Traditional Chinese Medicine in diabetic nephropathy.