CD14 and Salt-Sensitive Hypertension

CD14 和盐敏感性高血压

• 批准号: 10633269
• 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/10633269
• 关键词: Address; Animal Model; Antihypertensive Agents; Attenuated; Bone Marrow; Cardiovascular Diseases; Cell Separation; 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; Macrophage; 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; blood pressure elevation; cardiovascular risk factor; cytokine; experimental study; hemodynamics; hypertensive; hypertensives; in vivo; insight; 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.

总结 高血压是心血管、脑血管和肾脏疾病的主要可改变的危险因素， 是世界上导致疾病和死亡的最大的个体因素。盐敏感性高血压 占高血压人群30-50%的个体，其死亡率高于盐- 顽固性高血压并表现出肾终末器官损伤。我们最近发现了一种新的抗高血压药物 由分化簇14（CD 14）介导的机制，相对于 男性。CD 14是Toll样受体4（TLR 4）的共受体。有趣的是，CD 14在细胞中的表达 白细胞和血浆CD 14蛋白水平在心血管疾病和高血压中升高， 人类我们认为，肾脏巨噬细胞中的CD 14信号传导对抗TLR 4和铅的作用。 自由基和促炎细胞因子IL-1β的释放减弱，T细胞活化减弱， 减轻盐敏感性高血压。 这个项目是基于我们独特的（有点令人惊讶的）观察，即CD 14的遗传缺失， 其在喂食高盐的达尔盐敏感（SS）大鼠的肾脏中的巨噬细胞中上调，导致 促炎细胞因子IL-1β和活性氧释放增加。值得注意的是，我们观察到 缺乏CD 14（SSCD 14-/-）的雌性Dahl SS大鼠表现出盐敏感性高血压和肾损伤的放大， 与野生型同窝仔相比。进一步的研究表明，CD 14缺失的影响是依赖性的， 在造血细胞上，在雌性中扩增，并在缺乏吞噬NADPH氧化酶2（NOX 2）的大鼠中消除。 这些令人兴奋的数据表明，CD 14在盐敏感性肿瘤的发展中具有意想不到的性别依赖性作用。 高血压和肾损害。这项提议将检验以下假设： 肾脏巨噬细胞中的CD 14导致肾脏中T细胞活化减少，减弱盐敏感性。 高血压和减少肾终末器官损伤。这一假设将在三个具体目标中得到解决。 目的1将阐明CD 14对盐敏感性高血压的保护作用以及CD 14对盐敏感性高血压的保护作用。 相关的肾损伤涉及巨噬细胞中TLR 4介导的信号传导的抑制。目标2将解决 假设巨噬细胞中升高NOX 2介导了高盐饮食的Dahl SS大鼠的血压升高， 这种作用在雌性中被CD 14减弱，在雄性中被TLR 4放大。目标3将阐述以下假设： TLR 4的促高血压作用和CD 14的抗高血压作用是由相应的 自由基依赖性过程中压力性利尿钠和肾内血流动力学的变化 从巨噬细胞和T细胞中的NOX 2释放。该提案采用体外和体内方法， 解决这一假设使用独特的，基因工程大鼠品系开发的这项赠款，新的免疫 细胞转移方法和评估清醒大鼠血液动力学变量的最新方法。

项目成果

Dietary Protein, Chronic Salt-Sensitive Hypertension, and Kidney Damage.

• DOI: 10.34067/kid.0000000000000210
• 发表时间: 2023-08-01
• 期刊: Kidney360
• 作者: Mattson DL;Dasinger JH;Abais-Battad JM
• 通讯作者: Abais-Battad JM

Functional NADPH oxidase 2 in T cells amplifies salt-sensitive hypertension and associated renal damage.

T 细胞中的功能性 NADPH 氧化酶 2 会加剧盐敏感性高血压和相关的肾损伤。

• DOI: 10.1152/ajprenal.00014.2023
• 发表时间: 2023
• 期刊: American journal of physiology. Renal physiology
• 作者: Walton,SamuelD;Dasinger,JohnHenry;Burns,EmilyC;Cherian-Shaw,Mary;Abais-Battad,JustineM;Mattson,DavidL
• 通讯作者: Mattson,DavidL