脂肪因子ZAG通过Sp1对肾脏AT1受体的调节在高血压调控中的作用与机制研究

脂肪因子与高血压密切关联，探寻新的脂肪因子在血压调节中的作用具有重要价值。申报者前期发现锌α2糖蛋白（ZAG）可评价胰岛素抵抗水平，但ZAG是否可调控血压并不清楚。我们预实验发现高血压患者循环ZAG水平较正常组降低，且高血压患者血清ZAG与舒张压呈负相关。重要的是，我们首次利用外源性ZAG作用自发性高血压大鼠（SHR）后，发现其血压降低！且伴随尿钠排泄增加，提示肾脏排泄功能在ZAG调控血压中可能发挥作用！随后通过蛋白组学及转录组学筛选出AT1受体，给予外源性ZAG后SHR肾脏AT1受体转录及表达降低，伴随其上游转录因子Sp1水平也降低。因此提出科学假说：循环脂肪因子ZAG通过Sp1引起肾脏AT1受体减少，导致尿钠排泄增加，从而降低血压。本项目拟针对假说展开研究，通过ZAG基因敲除小鼠及外源性加入ZAG，正反两个方面探讨ZAG对血压及肾脏尿钠排泄的影响及其机制，为高血压的治疗提供新思路。

Adipokines are closely related to hypertension, and it is of great value to explore the role of new adipokine in regulation of blood pressure. The applicant found that zinc α2 glycoprotein (ZAG) can assess the level of insulin resistance, but it is not clear whether ZAG can regulate blood pressure. Our preliminary experiments found that the circulating ZAG level of hypertensive patients was lower than that of the normal group, and the serum ZAG of hypertensive patients was negatively correlated with diastolic blood pressure. Importantly, we used exogenous ZAG to act on spontaneously hypertensive rats (SHR) for the first time, we found that their blood pressure decreased! And with the increase in urinary sodium excretion, it suggests that the renal excretion function may play a role in regulation of blood pressure by ZAG! Subsequently, the AT1 receptor was screened by proteomics and transcriptomics. After the administration of exogenous ZAG, the transcription and expression of the AT1 receptor in the SHR kidney decreased, and the level of its upstream transcription factor Sp1 also decreased. Therefore, the scientific hypothesis is proposed: Circulating adipokine ZAG results in a decrease of renal AT1 receptors through Sp1, leads to an increase in urinary sodium excretion, blood pressure reduces ultimately. Based on the above hypothesis, through ZAG gene knockout mice and exogenous addition of ZAG, the effects and mechanism of ZAG on blood pressure and renal sodium excretion will be explored in both pros and cons, to provide new ideas for the treatment of hypertension.