盐诱导激酶2调控巨噬细胞活化在高盐诱导高血压中的作用机制研究

Inflammation plays an important role in the development of hypertension. Funded by the National Natural Science Foundation of China, we found that macrophage activation is involved in hypertensive vascular remodeling. Recently, we found that SIKs inhibitors attenuated high salt (8%Nacl)-induced elevated blood pressure, which was associated with reduction of renal macrophage infiltration and sodium hydrogen exchanger 3 (NHE3). Meanwhile, high salt enhanced SIK2 expression in macrophages, suggesting that the intervention may involve the expression of SIK2. Therefore, we hypothesized that high salt activates SIK2 signaling pathway in macrophages, which causes NHE3 dysfunction in renal tubular epithelial cell leading to elevated blood pressure. In this study, macrophage SIK2 knockout mice are used to prepare high salt-induced hypertension model and our study aims to explore: 1) high salt-induced changes of SIK2 expression in macrophages and disturbance of water and salt metabolism in hypertension. 2) mechanism of SIK2 signaling pathway activated by high salt in macrophage to regulate the expression and activity of NHE3 in renal tubular epithelial cells. 3) SIK2 regulating the activation of renal macrophages contributing to water and salt metabolism dysfunction and hypertension, providing a new intervention strategy for elucidating the pathogenesis of hypertension induced by high salt.

炎症反应在高血压发生发展中发挥至关重要的作用。在上一个青年项目资助下，我们发现巨噬细胞参与高血压血管重塑过程。近期我们发现高盐（8%NaCl）模型经盐诱导激酶（SIKs）抑制剂干预可以降低血压，伴随肾脏巨噬细胞及钠氢交换体3（NHE3）减少，同时高盐促进巨噬细胞SIK2表达增加，推测干预作用涉及SIK2。然而，SIK2是如何参与高血压及水盐代谢紊乱尚不清楚。因此本项目假设SIK2调控高盐激活的巨噬细胞作用于肾小管上皮细胞，促使NHE3功能紊乱引起血压升高。本项目旨在此基础上，以巨噬细胞特异性SIK2基因敲除小鼠为研究对象，制备高盐诱导高血压模型，研究1）高盐诱导巨噬细胞SIK2表达活性变化及高血压水盐代谢紊乱；2）巨噬细胞SIK2信号通路激活调控肾小管上皮细胞NHE3表达活性的机制；3）SIK2调控肾脏巨噬细胞活化参与水盐代谢紊乱导致高血压，为阐明高盐诱导高血压的发病机制提供新的干预策略。

炎症反应尤其是巨噬细胞激活在高血压及靶器官损伤的发生发展中发挥至关重要的作用。我们前期研究发现巨噬细胞参与高血压血管重塑过程。本项目基本按计划执行：证实盐诱导激酶2（SIK2）调控巨噬细胞激活参与AngII诱导的心肌肥大及纤维化过程，以及巨噬细胞SIK2调控盐诱导高血压的作用机制；发现转录因子KLF15通过其转录活性区域调控AngII诱导巨噬细胞浸润以及血管外膜重塑，以及KLF15调控IL-11表达参与AngII诱导的血管外膜纤维化及炎症反应，以及KLF15调控CXCL1/CXCR2轴介导巨噬细胞激活参与AngII诱导的心肌重塑，并发掘调控纤维化和炎症反应的新靶点（IL-11，CXCL1等）；探讨利钠肽C受体（NPR-C）通过调控肾脏钠氯转运体活性介导钠水潴留，从而参与AngII诱导的血压升高；揭示外膜成纤维细胞通过分泌VEGF调控滋养血管新生并促进巨噬细胞招募参与损伤诱导新生内膜形成。以上研究为防治高血压以及靶器官损伤乃至寻找新的治疗策略与干预靶点提供了理论依据。