Role of endothelin in hypertension-mediated inflammation and end-organ damage

项目总结 大量证据表明，经常食用高盐饮食的人患糖尿病的风险更大。 与低盐饮食的人相比，患心血管疾病(CVD)的人更多。此外，饮食 摄入高盐和相关的炎症在心血管疾病的发展中起着关键作用，如 作为高血压。特别是，T细胞与高血压的发生密切相关。然而，有一种 我们对盐介导的T细胞激活、终末器官损伤和 心血管疾病风险。 内皮素-1(ET-1)是一种有效的血管活性多肽，在高盐摄入后水平升高。肾 炎症是盐敏感型高血压的特征之一，而ET-1被认为具有促炎作用 在肾组织中的作用。事实上，人类T细胞表面表达ET-1受体(ETA和ETB)，并且 体外被ET-1激活。最近的报道表明，高盐可以诱导促炎因子的产生 T细胞产生的细胞因子。尽管许多研究表明肾脏ET-1系统是一个重要的 高钠摄入会导致血压升高、炎症和肾脏损害， ET-1介导这些效应的分子机制尚不清楚。此外，ET-1的参与 在肾脏方面，盐依赖型高血压时T细胞活化和靶器官损害需要研究。 高盐摄入增加了肾脏中几个细胞来源的ET-1的产生，尽管细胞 高盐时肾T细胞活化和分化的ET-1来源尚不清楚。 本建议旨在阐明参与控制肾脏病理生理学的新的分子途径。 与血压升高有关。这项建议将测试1)ET-1/ETA轴的激活导致 盐敏感型高血压患者肾脏T细胞活化与盐致肾损害和心血管疾病的关系 风险，以及2)血管内皮源性ET-1升高是肾损害的原因 食盐消耗量高。 在导师和科学顾问团队的帮助下，我将继续朝着我的长期目标前进 在免疫学和心脏-肾脏的交叉点上发展一个强大的独立研究项目 生理学，最终目标是将这些知识转化为改善人类健康的知识。如果获奖，这款K01 获奖将帮助我获得额外的培训，成为一名成功的基础科学研究人员 心肾生理学。

PROJECT SUMMARY Extensive evidence demonstrates that individuals that regularly consume high salt diet have a greater risk of developing cardiovascular diseases (CVD) compared to individuals on low salt diet. Moreover, dietary consumption of high salt and the associated inflammation have critical roles in the development of CVD, such as hypertension. Particularly, T cells are intimately linked to the development of hypertension. However there is a gap in our knowledge of the mechanisms involved in salt-mediated T cell activation, end-organ damage and CVD risk. Levels of endothelin-1 (ET-1), a potent vasoactive peptide, are elevated after high salt consumption. Renal inflammation is one of the hallmarks of salt-sensitive hypertension, and ET-1 is known to exert pro-inflammatory actions in renal tissue. In fact, human T cells express ET-1 receptors (ETA and ETB) on their surface and are activated by ET-1 in vitro. Recent reports demonstrate that high salt induces production of pro-inflammatory cytokines by T cells. Despite the many studies demonstrating that the renal ET-1 system is an important contributor to increased blood pressure, inflammation and kidney damage during high sodium intake, the molecular mechanisms by which ET-1 mediates these effects remain obscure. Further, the involvement of ET-1 in renal T cell activation and target organ damage during salt-dependent hypertension needs investigation. High salt consumption increases ET-1 production by several cellular sources in the kidney, although the cellular source of ET-1 mediating renal T cell activation and differentiation during high salt remains unclear. This proposal aims to elucidate novel molecular pathways involved in the control of the renal pathophysiology associated with increased blood pressure. This proposal will test that 1) activation of the ET-1/ETA axis leads to kidney T cell activation during salt-sensitive hypertension and results in salt-induced kidney damage and CVD risk, and 2) elevated vascular endothelium-derived ET-1 is responsible for the kidney damage observed during high salt consumption. With the help of my mentor and scientific advisory team, I will continue on the path toward my long-term goal of developing a strong and independent research program at the intersection of immunology and cardio-renal physiology, with the ultimate goal of translating this knowledge to improve human health. If awarded, this K01 award will help me to achieve extra training to become a successful basic science investigator in the field of cardio-renal physiology.