胰岛素抵抗通过T细胞表面SLAMF3介导的IL-17R/NF-κB通路引起肾脏足细胞损伤的机制研究

胰岛素抵抗可加重足细胞损伤促进糖尿病肾病进展，研究表明T细胞介导的免疫调控异常在其中发挥重要作用，具体机制尚不明确。前期实验中我们发现，T2DM患者外周血T细胞表面SLAMF3分子表达明显升高，RNA-seq提示SLAMF3高表达后IL-17信号通路活化，并有多种差异表达基因在肾脏疾病富集；同时，当高表达SLAMF3的T细胞与足细胞共培养时，会使足细胞NF-κB p65表达增加、nephrin表达减少。提示胰岛素抵抗可能引起T细胞表面SLAMF3高表达，促进IL-17释放，进而激活足细胞IL-17R/NF-κB通路，导致肾脏足细胞损伤并促进DKD发展。综上，本研究拟通过体内、外实验，深入探讨胰岛素抵抗情况下，T细胞表面SLAMF3介导的IL-17R/NF-κB通路在足细胞损伤及糖尿病肾病发生中的作用及机制，为T细胞调控异常促进糖尿病肾病进展提供新的理论依据；为糖尿病肾病的治疗提供可能靶点。

Insulin resistance can induce kidney podocyte injury, leading to the development and progression of diabetic kidney disease (DKD). Studies have shown that T cell-mediated immune dysregulation plays an important role in above process, however, the specific mechanism is unclear. According to our previous results, we found that the expression of SLAMF3 on peripheral blood T cell surface was significantly elevated in patients with T2DM. Furthermore, RNA-sequence analysis showed that elevated SLAMF3 expression could activate the IL-17 signaling pathway significantly. And there were many differentially expressed genes enriching in kidney disease. Next, we found that NF-κB p65 expression was upregulated and nephrin expression was reduced in podocytes after co-culturing with T cells which elevated SLAMF3 expression. All above results suggest that insulin resistance can induce elevated expression of SLAMF3 on T cell, which could promote IL-17 release. Then elevated IL-17 could activate IL–17R/NF-κB pathway in podocyte, eventually induce podocyte injury along with the development of DKD. In conclusion, we aimed to explore the mechanism of f SLAMF3-mediated IL-17R/NF-κB pathway in insulin resistance-induced podocyte injury and its relationship with the development of DKD in vitro and in vivo. The results will help to provide new theoretical basis for the T cell dysregulation to promote the progression of DKD; and to imply a new target for the treatment of DKD.