Role of pressure induced renal inflammation in salt-sensitive hypertension

压力诱发的肾脏炎症在盐敏感性高血压中的作用

• 批准号: 10201744
• 负责人: Louise Christine Evans
• 金额: $ 38.54万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10201744
• 关键词: Acceleration; Acids; Aldosterone; Blood Pressure; CCL4 gene; CCR1 gene; CCR5 gene; Cardiovascular Diseases; Cells; Citrates; Clinical; Collagen; Dahl Hypertensive Rats; Data; Data Analyses; Development; Disease; Duct (organ) structure; Epithelial Cells; Essential Hypertension; Exposure to; Fibrosis; Glomerular Filtration Rate; Home; Hypertension; Immune; Immune system; Infiltration; Inflammation; Inflammatory; Injury; Injury to Kidney; Kidney; Kidney Diseases; Left kidney; Link; Lymphocyte; Malignant - descriptor; Malignant Neoplasms; Metabolism; Morbidity - disease rate; Nephrons; Oxidative Phosphorylation; Oxidative Stress; Pathogenesis; Pathologic; Pathway interactions; Patients; Perfusion; Phase; Play; Prevalence; Production; Proteins; Proteinuria; RANTES; Rattus; Renal Hypertension; Renal Tissue; Renal function; Renal tubule structure; Right kidney; Risk Factors; Role; Secondary to; Sodium; Sodium Chloride; System; T-Lymphocyte; Tubular formation; Up-Regulation; Work; base; blood pressure regulation; chemokine; chemokine receptor; fatty acid metabolism; genetic association; high salt diet; hypertension treatment; immune activation; in vivo; macrophage; modifiable risk; mortality; neutrophil cytosol factor 67K; new therapeutic target; novel; overexpression; pressure; prevent; public health relevance; receptor; response; salt sensitive; salt sensitive hypertension; targeted biomarker; theories; transcriptome sequencing; transcriptomics

ABSTRACT Hypertension is a leading cause of global mortality and is the primary modifiable risk factor for renal and cardiovascular disease. In 50% of patients with essential hypertension, blood pressure increases in response to salt. Despite this, the mechanisms underlying salt-sensitive hypertension remain poorly understood. Our studies in Dahl salt-sensitive (SS) rats have shown that proteinuria is indicative of the initiation of salt-sensitive hypertension, whereas renal inflammation is involved in the amplification of the disease. To date, the link between proteinuria and renal inflammation in salt-sensitive hypertension has not been elucidated, moreover the mechanisms by which renal T-cells amplify salt-sensitive hypertension have not been fully determined. Based on our previous work and preliminary data we hypothesize that exposure of the renal tubule to excess protein (proteinuria) causes its “inflammatory activation” and the release of the chemokines CCL4 and CCL5. We anticipate that this tubular production of CCL4 and CCL5 initiates renal inflammation by attracting CCR1 and CCR5 positive immune cells to regions of injury. We hypothesize that once in the kidney, T-cells amplify hypertension by promoting renal injury, sodium retention and oxidative stress. Therefore, we predict that antagonism of CCR1 and CCR5 may provide a novel treatment for hypertension. Our hypothesis is supported by our compelling preliminary data indicating: 1) overexpression of CCL4 and CCL5 and their receptors, CCR1 and CCR5 in the hypertensive kidney of SS rats, 2) localization of CCL4 and CCL5 in the renal tubules of salt- sensitive rats fed high-salt for 12-days and 3) increased p67phox (indicative of oxidative stress) and col1a1 (indicative of fibrosis) in the kidneys of SS rats with T-cells relative to those without, in the absence of differences in blood pressure. This proposal has two Specific Aims: 1. Determine the role of the chemokines CCL4 and CCL5 and their receptors CCR1 and CCR5 in the initiation of renal inflammation during the development of salt- sensitive hypertension. 2. Use a unique pressure-matching approach in salt-sensitive (SSCD247+/+) and T-cell deficient (SSCD247-/-) rats to isolate the pathological effects of renal T-cells, in vivo, on renal function.

摘要 高血压是全球死亡率的主要原因，也是肾脏疾病的主要可改变风险因素， 心血管疾病在50%的原发性高血压患者中， 盐尽管如此，盐敏感性高血压的机制仍然知之甚少。我们的研究 在Dahl盐敏感（SS）大鼠中，已经显示蛋白尿指示盐敏感性的开始， 高血压，而肾脏炎症参与疾病的扩大。迄今为止， 盐敏感性高血压中蛋白尿和肾脏炎症之间的关系尚未阐明，此外， 肾T细胞放大盐敏感性高血压的机制尚未完全确定。基于 根据我们以前的工作和初步数据，我们假设肾小管暴露于过量的蛋白质 （蛋白尿）引起其“炎症激活”和趋化因子CCL 4和CCL 5的释放。我们 预期这种CCL 4和CCL 5的肾小管产生通过吸引CCR 1启动肾脏炎症， CCR 5阳性免疫细胞的损伤区域。我们假设一旦进入肾脏， 高血压通过促进肾损伤，钠潴留和氧化应激。因此，我们预测， CCR 1和CCR 5的拮抗可能为高血压提供新的治疗方法。我们的假设得到了支持 我们令人信服的初步数据表明：1）CCL 4和CCL 5及其受体CCR 1的过度表达 CCL_4和CCL_5在SS大鼠高血压肾组织中的定位; 高盐喂养12天的敏感大鼠和3）增加p67 phox（氧化应激的指示）和col 1a 1 在不存在差异的情况下，具有T细胞的SS大鼠的肾脏相对于不具有T细胞的SS大鼠的肾脏（指示纤维化）的变化。 在血压上。这项建议有两个具体目标：1。确定趋化因子CCL 4和 CCL 5及其受体CCR 1和CCR 5在盐发展期间引发肾脏炎症中的作用- 敏感性高血压2.在盐敏感（SSCD 247 +/+）和T细胞中使用独特的压力匹配方法 缺陷型（SSCD 247-/-）大鼠，以分离肾T细胞在体内对肾功能的病理作用。