运动干预是高血压非药物疗法的最有效方式之一，骨骼肌的内分泌作用愈加受到重视。我们前期发现SHR大鼠长期注射肌肉因子irisin可促尿钠排泄并降低血压。GRK4是调控肾脏尿钠排泄的重要激酶，并受c-Myc调控，我们预实验显示irisin下调SHR大鼠肾脏GRK4和c-Myc表达，提示其可能下调c-Myc影响GRK4表达。因irisin仅在蛋白水平影响c-Myc，故将研究重点放在c-Myc蛋白降解上，而泛素化为其降解的主要方式。生物信息学分析示irisin存在与泛素-蛋白酶体作用的DCAF结构域，免疫沉淀显示其可直接结合c-Myc。为此，我们提出假设：irisin可被RPT细胞摄入胞核，促进c-Myc降解，进而影响GRK4表达，发挥利尿排钠和降血压作用。本项目利用SHR及WKY大鼠、irisin过表达和敲除小鼠等进行实验，探讨irisin调节肾脏GRK4表达的机制，为高血压治疗提供理论基础。

Since exercise has become one of the most effective non-drug treatment for hypertension, researchers have paid more attention to the endocrine effects of skeletal muscle. Our previous studies have shown that irisin, a muscle endocrine factor, can reduce blood pressure and promote natruresis in SHR rats. Since the GRK4, which regulated by c-Myc in transcription level, has been known as the critical kinase in natruresis, while our preliminary experiments have shown that irisin can reduce both GRK4 and c-Myc in kidney of SHR rats, irisin might regulate GRK4 through reducing c-Myc. Because the irisin can only regulate c-Myc in protein level instead of transcription level, the degradation of c-Myc should be considered as the possible target of irisin regulation. Ubiquitination has been proved as the main modification in c-Myc degradation, while bioinformatical analysis have shown the DCAF domain, which taking function in ubiquitin-proteasome, also been found in irisin, and co-immunoprecipitation have shown irisin can combine with c-Myc directly. Thus, we suggest that irisin excreted by skeletal muscle can be taken by the nucleus of RPT cell, and can promote the ubiquitination and degradation of c-Myc which regulates expressing of GRK4, and, as a result, can improve nutruresis and reduce blood pressure. This project can explore the mechanism that irisin regulates expressing of GRK4 and can provide the theoretical basis of hypertension therapy, by experiments using SHR and WKY rats and experiments using over-expression irisin mice and irisin knock-out mice.