TKI靶向药致高血压是制约临床应用的重要原因，但其机制不清楚。GRK4是影响尿钠排泄和血压的重要激酶，我们发现舒尼替尼升血压同时，伴有GRK4表达增加；其致GRK4高表达可能与其影响GRK4磷酸化、降低GRK4蛋白降解有关。既往研究显示TKI可抑制Src激酶，由于Src激酶具有磷酸化GRK4的潜能，提示舒尼替尼可能通过抑制Src激酶、改变GRK4磷酸化程度和衰减能力，从而升高其表达。由于磷酸化是泛素化发生的化学修饰基础，信息学显示GRK4具有与20S蛋白酶体结合的泛素化位点，因此，我们推测“TKI抑制Src活性，降低肾脏GRK4磷酸化，抑制GRK4磷酸化触发的泛素化，从而提高GRK4表达，导致钠水重吸收增加和血压升高”。本课题拟采用GRK4转基因和敲除小鼠，分析GRK4在TKI致高血压中的作用，为TKI相关高血压的防治提供理论基础。

TKI-induced hypertension is the main reason that restricts the clinical application of TKI. It is necessary to determine the mechanism and find out the treatment. GRK4 is the key kinase that regulates the natriuresis and blood pressure. Sunitinib elevates blood pressure, induces sodium retention and increases the GRK4 expression, which is ascribed to the decreasing GRK4 degradation. GRK4 could be phosphorylated. Previous studies showed Src kinase could induce GRK2 phosphorylation, and GRK4 has the same phosphorylation site of GRK2, indicating GRK4 might be phosphorylated by Src. TKI inhibits the effect of Src. Therefore, Sunitinib might suppress the effect of Src on GRK4 phosphorylation, decreases the GRK4 degradation and leads to GRK4 overexpression. The ubiquitination might be depended on phosphorylation. Previous studies showed GRK2 ubiquitination and degradation is regulated by 20S proteasome, while GRK4 has the same ubiquitination site of GRK2, indicating GRK4 degradation is regulated by 20S proteasome. Thus, we infer that TKI inhibits Src activity, decreases the phosphorylation of renal GRK4, suppresses the GRK4 phosphorylation associated ubiquitination, reduces GRK4 degradation and results in increased renal reabsorption and elevated blood pressure. In the present study, the GRK4 transgenic and knockout mice are used to analyze the role of GRK4 phosphorylation and ubiquitination in TKI-induced hypertension. GRK4 might be the potential target for the treatment of TKI-associated hypertension.