转录因子调控钠尿肽受体C（NPR3）参与高血压动脉硬化发生机制及干预策略研究

Hypertension-induced arterial stiffness is the pathophysiological basis of various target organ damage. To clarify the mechanism of hypertension is very important. Salt contributes to hypertension and arterial stiffness, while genome-wide association studies (GWAS) found the risk associated gene NPR3 was related to water and salt metabolism, its role on the pathogenesis of hypertension and arterial stiffness remains unclear. In this study, we hypothesizes that NPR3 mediates the disorder of water and salt metabolism, and the activation of transcription factors and their signaling pathways, all interact with each other participating in the hypertension and arterial stiffness. Our previous studies have found that high salt induced alternation of NPR3 and transcription factor Klf15 in the rat model of hypertension, and the changes in collagen composition in the vascular wall. In this study, we focus on NPR3 and transcription factor KLF15, and our study aims to: 1) establish high salt and angiotensin II + salt hypertensive model to elucidate the mechanism of NPR3 mediating hypertension and arterial stiffness. 2) examine the network mechanism of the interaction of Klf15 and TGF-beta / Smads in the regulation of NPR3 3) investigate Klf15 regulation of NPR3 as a target for the intervention of hypertension and arterial stiffness. 4) verify the relationship between NPR3, Klf15 and blood pressure as well as the intermediate phenotype in the pathogenesis of hypertension and arterial stiffness by use of an established cohort, and explore new intervention strategies for the intervention of hypertension and arterial stiffness.

高血压导致的动脉硬化是靶器官损伤的病理生理学基础，阐明其机制至关重要。已知盐是参与高血压动脉硬化的重要因素，前期高血压全基因组关联研究（GWAS）发现钠尿肽受体C（NPR3）与水盐代谢相关，但其是否参与高血压动脉硬化过程并不清楚。本项目假设NPR3介导水盐代谢紊乱，与高盐等因素激活的转录因子及信号通路交互作用共同参与高血压动脉硬化过程。我们近期发现高盐诱导NPR3及转录因子Klf15表达变化，并参与血管壁胶原成分改变。本研究进一步以NPR3及Klf15为切入点，研究1）高盐及血管紧张素II+盐高血压模型中NPR3参与调控高血压动脉硬化过程；2）Klf15与TGF-β/Smads相互作用调控NPR3的网络机制；3）探讨Klf15调控NPR3为靶点干预高血压动脉硬化的整体研究；4）利用已建立的研究队列验证NPR3和Klf15与血压及相关中间表型在高血压动脉硬化中的作用，并探讨新的干预策略。

盐是参与高血压动脉硬化的重要因素，阐明水盐代谢介导的血管稳态失衡作用机制对防治高血压血管损伤至关重要。本项目前期高血压全基因组关联研究（GWAS）发现钠尿肽受体C（NPR3）与水盐代谢相关，但其是否参与高血压动脉硬化过程并不清楚。因此本研究以水盐代谢对血压的影响为研究方向，以肾脏钠离子通道为研究切入点，发现1）NPR3影响肾脏水盐代谢调控血压的分子机制；2）转录抑制因子KLF15通过其激活结构域改善血管重塑的作用机制；3）证实天麻钩藤饮治疗隐匿性高血压的安全性、有效性；4）建立了NPR3与血压、动脉硬化相关联的中间临床表型，分析影响这一中间表型的的环境与遗传因素。以上研究为发现水盐代谢调控高血压血管病变的治疗策略和干预靶点提供了理论基础。