新型脂肪分泌因子Metrnl对糖尿病肾病治疗作用及分子机制研究

The secretory adipokine, Metrnl, secreted by adipose tissue, is an important member of endocrine factors which is discovered in recent years. This cytokine can achieve all the tissues and organs via the whole body blood circulation and exerts anti-inflammatory immune response and promotes energy expenditure effects. Our previous study revealed that the expression of Metrnl was dramatically enhanced in individuals suffering from Diabetic nephropathy , which was significantly related to the clearance efficiency of blood urea nitrogen and serum creatinine clearance rate. Moreover, we carried out a tail vein injection of the adenovirus Metrnl into db/db mice and confirmed the role of Metrnl in ameliorating insulin resistance and the pathological of DN mice. Based on the well-established that the occurrence of DN is associated with the release of inflammatory factors, we studied the role of Metrnl in development of DN and its corresponding influence in this study. Furthermore, we applied clinical study，animal and cell experiments to explore the mechanisms of Metrnl regulating inflammatory signalings and seek for potential drug targets for DN therapy.

脂肪分泌因子Metrnl是近年来新发现的一类重要的内分泌蛋白，由脂肪组织分泌后经血循环到达全身各组织器官，发挥抗炎症免疫反应和促进机体能量消耗的作用。近期我们课题组的研究发现，糖尿病肾病（DN）患者血清Metrnl水平明显升高，且与血尿素氮及肌酐清除率显著相关；同时我们采用过表达腺病毒对db/db小鼠尾静脉注射的研究也发现Metrnl对DN小鼠的胰岛素抵抗和糖尿病肾病具有改善作用。既往研究认为糖尿病肾病的发病与炎症免疫反应密切相关，因此本项目拟通过临床、动物及细胞实验，探索Metrnl在DN发生发展中的作用，并观察Metrnl对炎症信号通路的影响，为DN的治疗提供新的药物靶点及新思路。

脂肪分泌因子Metrnl是近年来新发现的一类重要的内分泌蛋白，由脂肪组织分泌后经血循环到达全身各组织器官，发挥抗炎症免疫反应和促进机体能量消耗的作用。近期我们课题组的研究发现，糖尿病肾病（DN）患者血Metrnl水平明显升高，且与血尿素氮及肌酐清除率显著相关；同时我们采用过表达腺病毒对db/db小鼠尾静脉注射的研究也发现Metrnl对DN小鼠的胰岛素抵抗和糖尿病肾病具有改善作用。既往研究认为糖尿病肾病的发病与免疫炎症密切相关，本项目通过临床、动物及细胞实验，发现DN患者血清 Metrnl 水平明显升高，2 型糖尿病血清 Metrnl 水平与 UACR 和 MCP-1 呈正相关，与 eGFR呈负相关，血清 Metrnl 有望成为DN的新型生物标志物，具有反映DN病情进展和炎症反应的优势；上调模型小鼠肾脏 Metrnl 表达水平可改善小鼠肾功能及肾脏病理损伤，可能有望在将来成为治疗 2 型糖尿病肾脏损伤性疾病的新靶点；Metrnl 肾脏保护作用可能与下调 2 型糖尿病小鼠肾脏组织 TGF-β1/ Smads信号通路分子表达，抑制α-SMA 等纤维化分子表达有关。以上结果将有助于阐明 Metrnl 在 DN 发病中的作用，为早期预测 DN 发生发展提供新的生物标记，同时为治疗 DN 及研发新型药物提供新思路和新方法。