ROLE OF SPHINGOSINE KINASE 1 IN REGULATION OF VASCULAR TONE BY ANGIOTENSIN II

鞘氨醇激酶 1 在血管紧张素 II 调节血管张力中的作用

• 批准号: 8168052
• 负责人: Hesham M. El-Shewy
• 金额: $ 13.14万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8168052
• 关键词: Angiotensins; Blood Vessels; Characteristics; Chronic; Chronic Kidney Failure; Computer Retrieval of Information on Scientific Projects Database; Congestive Heart Failure; Coronary heart disease; Data; EGF gene; EGFR inhibition; Epidermal Growth Factor Receptor; Feedback; Functional disorder; Funding; Grant; Homeostasis; Hypertension; Institution; Kidney; Link; Measures; Mediating; Morbidity - disease rate; Mus; Oryctolagus cuniculus; Pathway interactions; Pattern; Perfusion; Phase; Play; Production; Regulation; Renin-Angiotensin System; Reporting; Research; Research Personnel; Resources; Risk; Role; SPHK1 enzyme; Source; Sphingosine; Stroke; Structure; Testing; Transactivation; United States National Institutes of Health; arteriole; base; blood pressure regulation; hemodynamics; hypertension control; in vivo; inhibitor/antagonist; insight; mortality; novel therapeutic intervention; research study; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Hypertension is a chronic condition associated with increased risk of mortality and morbidity from stroke, coronary heart disease, congestive heart failure, and chronic renal disease. Difficulty in controlling hypertension is due, in part, to the complexity of the pathophysiology of hypertension. In addition to the involvement of multiple pathways and feedback mechanisms, hypertension is often associated with other pathological conditions such as renal dysfunction, which is tightly linked to the renin-angiotensin system (RAS). Angiotensin (AngII), an important regulator of RAS, plays a critical role in regulation of blood pressure and volume homeostasis. These effects are mediated mainly via Ca2+ mobilization. Investigators reported the involvement of sphingosine kinase1 (SK1) in the mobilization of intracellular Ca2+. However, the exact mechanism is poorly understood. Here, we tested whether SK1 plays a role in AngII-stimulated Ca2+ release and regulating vascular tone. Our early observation using FLIPR to measure the intracellular Ca2+ levels indicated a characteristic pattern of AngII induced increase in intracellular Ca2+ level, an immediate peak followed by a sustained Ca2+ release. Additionally, selective inhibition of EGFR by AG1478 or the SK1 inhibitor, (DMS) inhibited the second phase. Also, AngII and EGF increased endogenous SK1 activity and enhanced production of S1P. Deletion of SK1 or DMS treatment abrogated EGF-induced intracellular Ca2+ elevation. Moreover, perfusion of the arteriole of the isolated rabbit glomerular structure with either AG1478 or DMS blocked the sustained elevation of intracellular Ca2+ and pressor response of Ang II. In vivo experiments performed on wild type and SK1-/- mice revealed that deletion of SK1 reverses the effect of AngII on GFR. Based on our data we propose to elucidate the role of EGFR transactivation and SK1/S1P in AngII-dependent intracellular Ca2+ mobilization, vascular tone, and renal hemodynamics. This study will enable us to gain important insight into the pathophysiology of hypertension and may provide novel therapeutic interventions.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 高血压是一种慢性疾病，与中风、冠心病、充血性心力衰竭和慢性肾病的死亡率和发病风险增加相关。控制高血压的困难部分是由于高血压病理生理学的复杂性。除了涉及多种途径和反馈机制外，高血压还常常与其他病理状况相关，例如与肾素-血管紧张素系统（RAS）密切相关的肾功能障碍。血管紧张素 (AngII) 是 RAS 的重要调节剂，在血压和容量稳态的调节中发挥着关键作用。这些作用主要通过 Ca2+ 动员介导。研究人员报告了鞘氨醇激酶 1 (SK1) 参与细胞内 Ca2+ 的动员。然而，人们对确切的机制知之甚少。在这里，我们测试了 SK1 是否在 AngII 刺激的 Ca2+ 释放和调节血管张力中发挥作用。我们使用 FLIPR 测量细胞内 Ca2+ 水平的早期观察表明，AngII 诱导细胞内 Ca2+ 水平增加的特征模式，立即达到峰值，然后持续释放 Ca2+。此外，AG1478 或 SK1 抑制剂 (DMS) 对 EGFR 的选择性抑制抑制了第二阶段。此外，AngII 和 EGF 还增加了内源性 SK1 活性并增强了 S1P 的产生。 删除 SK1 或 DMS 治疗可消除 EGF 诱导的细胞内 Ca2+ 升高。此外，用 AG1478 或 DMS 灌注离体兔肾小球结构的小动脉可阻断细胞内 Ca2+ 的持续升高和 Ang II 的升压反应。对野生型和 SK1-/- 小鼠进行的体内实验表明，SK1 的缺失可逆转 AngII 对 GFR 的影响。根据我们的数据，我们建议阐明 EGFR 反式激活和 SK1/S1P 在 AngII 依赖性细胞内 Ca2+ 动员、血管张力和肾血流动力学中的作用。这项研究将使我们能够深入了解高血压的病理生理学，并可能提供新的治疗干预措施。