Renal Infiltration of Immune Cells Mediates Hypertension

项目2将研究肾髓质中浸润免疫细胞在盐敏感性高血压和肾损伤发病机制中的作用。初步和已发表的数据表明，在遗传和实验性大鼠疾病模型中，盐敏感性高血压与广泛的肾损伤、免疫细胞浸润到肾脏中以及肾内血管紧张素II（ANGII）水平升高相关。 有趣的是，免疫系统或ANGII受体的药理学阻断减弱了这些疾病模型中高血压和肾损伤的发展。此外，免疫抑制药物直接进入肾髓质间质空间的管理降低了高血压的严重程度，表明免疫细胞浸润在肾髓质是重要的盐敏感性高血压的病理生理。使用这些新的数据作为理论基础和独特的综合实验 在Dahl盐敏感（SS）大鼠中，在暴露于高盐饮食（4%NaCl）后动脉血压初始升高后，免疫细胞浸润到肾髓质中介导了高血压和肾脏疾病的进一步发展，并且在正常大鼠中，在从肾缺血-再灌注损伤明显恢复后发生的盐敏感性高血压中，我们将检验这一假设。我们 进一步提出免疫细胞通过释放ANGII起作用，ANGII用于增加高血压和肾损伤的严重性。这一新的假设将在三个具体目标中得到解决。目的1将确定免疫细胞浸润到肾髓质间质空间的重要性，在遗传和实验性盐敏感性高血压的第二阶段。目的2将确定浸润免疫细胞在实验和遗传形式中合成和释放ANGII进入肾脏的能力， 盐敏感性高血压目的3将确定肾脏浸润免疫细胞对肾脏血流动力学的作用，以及在实验性和遗传性盐敏感性高血压中肾脏对钠和水的处理。

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.