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将研究肾髓质中的免疫细胞在肾炎发病机制中的作用。 盐敏感型高血压和肾脏损伤。初步和已公布的数据表明，对盐敏感 遗传性和实验性大鼠高血压均与肾脏广泛相关 损伤，免疫细胞渗入肾脏，肾内血管紧张素II(AngII)水平增加。 有趣的是，免疫系统或血管紧张素Ⅱ受体的药理阻断会减弱 在这些疾病模型中，高血压和肾脏损害的发展。此外，管理 直接进入肾髓质间隙的免疫抑制药物可降低肾小球硬化的严重程度。 提示肾髓质内免疫细胞的浸润在高血压的病理生理过程中起重要作用。 盐敏性高血压。利用这些新颖的数据作为理论基础和独特的综合实验 方法，我们将检验这样一种假设，即免疫细胞在肾髓质中的渗透 暴露于高盐饮食(4%NaCI)后动脉血压的初始升高介导了进一步的 Dahl盐敏感型(SS)大鼠和盐敏感型大鼠高血压和肾脏疾病的发展 正常大鼠肾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，免疫细胞通过释放血管紧张素转换酶来起作用，这有助于增加高血压的严重性 高血压和肾脏损伤。这一新的假设将在三个具体目标中得到解决。目标1将 确定免疫细胞在继发性肾间质病变中的重要性 盐敏感型高血压的遗传期和实验期。目标2将决定 以实验性和遗传性肾炎的形式渗透免疫细胞合成和释放血管紧张素转换酶Ⅱ到肾脏 盐敏性高血压。目标3将确定肾脏中浸润性免疫细胞在肾脏中的作用 实验性和遗传性盐敏感型患者的血流动力学和肾脏对钠和水的处理 高血压。