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

内皮素在高血压介导的炎症和终末器官损伤中的作用

• 批准号: 10579998
• 负责人: Carmen De Miguel
• 金额: $ 15.26万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10579998
• 关键词: Advisory Committees; Albumins; Applications Grants; Autoimmune Diseases; Award; Basic Science; Cardiovascular Diseases; Cell Differentiation process; Chronic Disease; Consumption; Development; Disease; Economic Burden; Endothelin; Endothelin A Receptor; Endothelin-1; Endothelium; Excretory function; Fibrosis; Functional disorder; Goals; Health; Health system; Histologic; Human; Hypertension; Immune system; Immunology; In Vitro; Individual; Inflammation; Inflammatory; Intake; Investigation; Kidney; Kidney Diseases; Knock-out; Knockout Mice; Knowledge; Link; Mediating; Mentored Research Scientist Development Award; Mentors; Modeling; Molecular; Mus; Organ; Pathway interactions; Peptides; Phenotype; Physiological; Physiology; Play; Production; Proteins; Rattus; Receptor Activation; Renal Hypertension; Renal Tissue; Reporting; Research; Research Personnel; Risk; Role; Scheme; Sodium; Sodium Chloride; Sodium-Restricted Diet; Source; Surface; System; T cell differentiation; T cell infiltration; T-Cell Activation; T-Lymphocyte; TNF gene; Testing; Training; Translating; Transplantation; Vascular Endothelial Cell; Vascular Endothelium; blood pressure elevation; cardiovascular disorder risk; career; career development; comparison control; cytokine; dietary; dietary salt; glomerulosclerosis; high salt diet; improved; in vivo; interest; interstitial; kidney cortex; nephrogenesis; novel; organ injury; programs; receptor; receptor expression; receptor function; renal damage; salt intake; salt sensitive hypertension; urinary

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.

项目摘要 大量的证据表明，经常食用高盐饮食的人患糖尿病的风险更大。 发展心血管疾病（CVD）相比，个人低盐饮食。此外，饮食 高盐的消耗和相关的炎症在CVD的发展中起着关键作用， 高血压特别是，T细胞与高血压的发展密切相关。但有 我们对盐介导的T细胞活化、终末器官损伤和 CVD风险。 内皮素-1（ET-1）是一种有效的血管活性肽，其水平在高盐摄入后升高。肾 炎症是盐敏感性高血压的标志之一，并且已知ET-1发挥促炎作用。 对肾组织的作用。事实上，人T细胞在其表面上表达ET-1受体（ETA和ETB），并在其细胞内表达。 ET-1在体外激活。最近的报道表明，高盐诱导促炎性细胞因子的产生， T细胞的细胞因子。尽管许多研究表明，肾脏ET-1系统是一个重要的 在高钠摄入期间， ET-1介导这些作用的分子机制仍不清楚。此外，ET-1的参与 盐依赖性高血压时肾脏T细胞活化和靶器官损害需要进一步研究。 高盐消耗增加了肾脏中几种细胞来源的ET-1产生，尽管这些细胞来源的ET-1在肾脏中的表达是不稳定的。 在高盐期间，ET-1介导肾T细胞活化和分化的来源仍不清楚。 该建议旨在阐明参与肾脏病理生理控制的新分子途径 与血压升高有关。该提议将测试1）ET-1/ETA轴的激活导致 盐敏感性高血压时肾脏T细胞活化并导致盐诱导的肾损伤和CVD 风险，和2）血管内皮衍生的ET-1升高是造成肾损伤的原因。 高盐消耗。 在我的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， 在免疫学和心肾医学的交叉领域发展强大而独立的研究计划 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，此K 01 该奖项将帮助我获得额外的培训，成为一个成功的基础科学研究领域的 心肾生理学