CD14 and Salt-Sensitive Hypertension

CD14 和盐敏感性高血压

• 批准号: 10522446
• 负责人: David L. Mattson
• 金额: $ 49.8万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10522446
• 关键词: Address; Animal Model; Antihypertensive Agents; Attenuated; Bone Marrow; Cardiovascular Diseases; Cells; Cerebrovascular Disorders; Clinical; Conscious; Dahl Hypertensive Rats; Data; Development; Disease; Diuresis; Exhibits; Female; Free Radicals; Genetic; Genetic Engineering; Grant; Hematopoietic; Human; Hypertension; Immune; Immunity; In Vitro; Individual; Inflammation; Inflammatory; Intake; Interleukin-1 beta; Kidney; Kidney Diseases; Knowledge; Lead; Leukocytes; Mediating; Methodology; Modeling; NADPH Oxidase; Natriuresis; Organ; Pathogenesis; Phagocytes; Plasma; Population; Process; Production; Proteins; Rat Strains; Rattus; Reactive Oxygen Species; Resistance; Resistant Hypertension; Risk Factors; Role; Signal Transduction; Sodium Chloride; T cell therapy; T-Cell Activation; T-Lymphocyte; TLR4 gene; Testing; Therapeutic; Work; base; blood pressure elevation; cardiovascular risk factor; cytokine; experimental study; hemodynamics; hypertensive; in vivo; insight; macrophage; male; modifiable risk; mortality; neutrophil cytosol factor 67K; novel; pressure; protective effect; receptor; renal damage; response; salt sensitive; salt sensitive hypertension; saluretic; sex

SUMMARY Hypertension is a primary modifiable risk factor for cardiovascular, cerebrovascular, and renal disease, and is the largest individual contributing factor to disease and mortality in the world. Salt-sensitive hypertensive individuals, who comprise 30-50% of the hypertensive population, have greater mortality than subjects with salt- resistant hypertension and exhibit renal end-organ damage. We recently discovered a novel anti-hypertensive mechanism that is mediated by Cluster of Differentiation 14 (CD14) and enhanced in females relative to males. CD14 is a co-receptor with Toll Like Receptor 4 (TLR4). Interestingly, the expression of CD14 in leukocytes and level of plasma CD14 protein are increased in cardiovascular disease and hypertension in humans. We propose that CD14 signaling in macrophages in the kidney opposes the effects of TLR4 and leads to the attenuated release of free radicals and the proinflammatory cytokine Il-1β, blunted T cell activation, and attenuated salt-sensitive hypertension. This project is based upon our unique (and somewhat surprising) observation that genetic deletion of CD14, which is upregulated in macrophages in the kidney of Dahl Salt-Sensitive (SS) rats fed high salt, leads to increased release of the proinflammatory cytokine Il-1β and reactive oxygen species. Remarkably, we observed that female Dahl SS rats lacking CD14 (SSCD14-/-) exhibit amplified salt-sensitive hypertension and renal damage compared to wild type littermates. Further study demonstrated that the effects of CD14 deletion are dependent on hematopoietic cells, amplified in females, and eliminated in rats lacking phagocytic NADPH oxidase 2 (NOX2). These exciting data indicate an unexpected, sex-dependent role of CD14 in the development of salt-sensitive hypertension and renal damage. This proposal will test the hypothesis that the anti-hypertensive effects of CD14 in macrophages in the kidney lead to decreased activation of T cells in the kidney, attenuated salt-sensitive hypertension, and decreased renal end-organ damage. The hypothesis will be addressed in three specific aims. Aim 1 will address the hypothesis that the protective effects of CD14 against salt-sensitive hypertension and associated renal damage involve inhibition of TLR4-mediated signaling in macrophages. Aim 2 will address the hypothesis that elevated NOX2 in macrophages mediate elevated blood pressure in Dahl SS rats fed high salt, an effect attenuated in females by CD14 and amplified in males by TLR4. Aim 3 will address the hypothesis that the pro-hypertensive effects of TLR4 and the anti-hypertensive effects of CD14 are mediated by corresponding changes in pressure natriuresis-diuresis and intrarenal hemodynamics in a process dependent upon free radicals released from NOX2 in macrophages and T cells. The proposal employs in vitro and in vivo approaches to address the hypothesis using unique, genetically-engineered rat strains developed for this grant, novel immune cell transfer approaches, and state-of-the art methodology to assess hemodynamic variables in conscious rats.

概括 高血压是心血管，脑血管和肾脏疾病的主要可修改风险因素，是 最大的个人促成了世界上疾病和死亡率的因素。盐敏感高血压 完成高血压人口的30-50％的个人比患有盐的受试者具有更大的死亡率 耐药性高血压和裸露的肾脏端管损伤。我们最近发现了一种新颖的抗高血压 由分化14（CD14）簇介导的机制，而女性则相对于女性的增强 男性。 CD14是一种具有收费（TLR4）的TOLL的共受体。有趣的是，CD14在 在心血管疾病和高血压中，白细胞和血浆CD14蛋白水平增加 人类。我们建议肾脏中巨噬细胞中的CD14信号传导反对TLR4的影响，并导致 自由基的释放和促炎性细胞因子IL-1β的释放，T细胞激活和 盐敏感的高血压减弱。 该项目基于我们独特的（有些令人惊讶的）观察结果，即CD14的遗传缺失， 在达尔盐敏感（SS）大鼠喂养高盐的巨噬细胞中，这是在上调的 促炎细胞因子IL-1β和活性氧的释放增加。值得注意的是，我们观察到 那位缺乏CD14（SSCD14 - / - ）暴露的扩增盐敏感性高血压和肾脏损伤的女性DAHL SS大鼠 与野生型同窝仔相比。进一步的研究表明，CD14缺失的影响取决于 在造血细胞上，在女性中扩增，并在缺乏吞噬细胞NADPH氧化物2（NOX2）的大鼠中消除。 这些令人兴奋的数据表明，CD14在盐敏感的发展中起意外的性别依赖性作用 高血压和肾脏损害。该提议将检验以下假设 肾脏中巨噬细胞中的CD14导致肾脏中T细胞的精制激活，盐敏感 高血压，并改善肾脏最终器官损伤。该假设将以三个具体目的解决。 AIM 1将解决以下假设：CD14对盐敏感高血压的受保护作用和 相关的肾脏损伤涉及在巨噬细胞中抑制TLR4介导的信号传导。 AIM 2将解决 假设巨噬细胞中NOX2升高培养基升高的DAHL SS大鼠的血压升高， CD14在女性中衰减的作用，并被TLR4在男性中扩增。 AIM 3将解决以下假设 TLR4和CD14的抗高血压作用的促甲状管拉力作用是通过相应的 在自由基的过程中，压力纳地尿和肾内血流动力学的变化变化 从巨噬细胞和T细胞中从NOX2释放。提案员工在体外和体内方法 使用独特的，遗传工程的大鼠菌株为这项赠款开发的新型免疫力来解决该假设 细胞转移方法以及评估有意识大鼠血液动力学变量的最新方法论。