Renal Infiltration of Immune Cells Mediates Hypertension

免疫细胞的肾浸润介导高血压

• 批准号: 7389280
• 负责人: David L. Mattson
• 金额: $ 32.02万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7389280
• 关键词: Address; Angiotensin II; Angiotensin II Receptor; Attenuated; Blood Pressure; Cells; Constriction procedure; Dahl Hypertensive Rats; Data; Development; Diet; Disease; Disease model; Diuresis; Elevation; Event; Experimental Genetics; Experimental Models; Exposure to; Free Radicals; Functional disorder; Generations; Genetic; Hepatolenticular Degeneration; Hypertension; Immune; Immune system; Immunosuppressive Agents; Infiltration; Injury; Intake; Kidney; Kidney Diseases; Lead; Maintenance; Mediating; Mediator of activation protein; Modeling; Natriuresis; Numbers; Organ; Pathogenesis; Pharmaceutical Preparations; Phase; Protocols documentation; Publishing; Rattus; Recovery; Renal Hypertension; Renal Tissue; Renal function; Reperfusion Injury; Role; Severities; Sodium; Sodium Chloride; Symptoms; Testing; Tissues; Tubular formation; Water; day; feeding; hemodynamics; interstitial; kidney medulla; novel; pressure; renal ischemia; research study; salt sensitive

Project 2 will examine the role of infiltrating immune cells in the renal medulla in the pathogenesis of salt-sensitive hypertension and renal injury. Preliminary and published data indicate that salt-sensitive hypertension in both a genetic and an experimental rat model of disease is associated with extensive renal injury, infiltration of immune cells into the kidney, and increased intrarenal angiotensin II (ANGII) levels. Interestingly, pharmacological blockade of the immune system or of ANGII receptors attenuates the development of hypertension and kidney damage in these disease models. Furthermore, administration of immunosuppressive drugs directly into the renal medullary interstitial space decreases the severity of hypertension, indicating that immune cell infiltration in the renal medulla is important in the pathophysiology of salt-sensitive hypertension. Using these novel data as a rationale and a unique integrative experimental approach, we will test the hypothesis that the infiltration of immune cells into the renal medulla following an initial increase in arterial blood pressure after exposure to a high salt diet (4% NaCI) mediates the further development of hypertension and kidney disease in Dahl Salt-Sensitive (SS) rats and in the salt-sensitive hypertension that occurs following apparent recovery from renal ischemia-reperfusion injury in normal rats. We further propose that the immune cells act by releasing ANGII which serves to increase the severity of hypertension and renal damage. This novel hypothesis will be addressed in three Specific Aims. Aim 1 will determine the importance of immune cell infiltration into the renal medullary interstitial space in the secondary phase of genetic and experimental forms of salt-sensitive hypertension. Aim 2 will determine the ability of infiltrating immune cells to synthesize and release ANGII into the kidney in experimental and genetic forms of salt-sensitive hypertension. Aim 3 will determine the role of infiltrating immune cells in the kidney on renal hemodynamics and the renal handling of sodium and water in experimental and genetic forms of salt-sensitive hypertension.

项目2将检查浸润免疫细胞在肾髓质中的作用 盐敏感的高血压和肾脏损伤。初步和已发布的数据表明盐敏感 遗传和实验大鼠疾病模型的高血压与广泛的肾脏有关 损伤，免疫细胞浸润到肾脏中，并增加了肾内血管紧张素II（ANGII）水平。 有趣的是，免疫系统或ANGII受体的药理阻滞可减弱 这些疾病模型中高血压和肾脏损害的发展。此外，管理 免疫抑制药物直接进入肾脏髓质间隙空间可降低 高血压，表明肾脏髓质中的免疫细胞浸润在病理生理学中很重要 盐敏感高血压。使用这些新型数据作为基本原理和独特的综合实验 方法，我们将检验以下假设：在 暴露于高盐饮食（4％NACI）后，动脉血压的初始升高进一步介导 DAHL盐敏感（SS）大鼠的高血压和肾脏疾病的发展以及盐敏感的 正常大鼠中肾脏缺血再灌注损伤明显恢复后发生的高血压。我们 进一步提出，免疫细胞通过释放ANGII来起作用，这有助于增加 高血压和肾脏损害。这个新颖的假设将以三个特定目的解决。目标1意志 确定免疫细胞浸润到继发肾脏髓质空间中的重要性 盐敏感高血压的遗传和实验形式的阶段。 AIM 2将决定 浸润免疫细胞以实验和遗传形式合成并释放Angii进入肾脏 盐敏感高血压。 AIM 3将确定浸润免疫细胞在肾脏上的作用 血液动力学以及对盐敏感的实验和遗传形式中钠和水的肾脏处理 高血压。