Renal Infiltration of Immune Cells Mediates Hypertension

项目2将研究肾髓质中渗入的免疫细胞在盐敏感型高血压和肾脏损伤发病机制中的作用。初步和已发表的数据表明，在遗传性和实验性大鼠疾病模型中，盐敏感型高血压与广泛的肾脏损伤、免疫细胞向肾脏的渗透以及肾内血管紧张素II(AngII)水平的增加有关。 有趣的是，在这些疾病模型中，对免疫系统或血管紧张素受体的药理阻断可以减缓高血压和肾脏损害的发展。此外，将免疫抑制药物直接注入肾髓质间隙可降低高血压的严重程度，表明肾髓质免疫细胞的浸润在盐敏感型高血压的病理生理过程中起重要作用。利用这些新颖的数据作为理论基础和独特的综合实验 我们将验证这样一种假设，即在高盐饮食(4%NaCI)暴露后动脉血压开始升高后，免疫细胞向肾髓质的渗透介导了Dahl盐敏感型(SS)大鼠高血压和肾脏疾病的进一步发展，以及在正常大鼠肾脏缺血再灌注损伤明显恢复后发生的盐敏感型高血压的进一步发展。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，血管紧张素转换酶有助于增加高血压和肾脏损害的严重程度。这一新的假设将在三个具体目标中得到解决。目的1将确定在遗传性和实验性盐敏感型高血压的第二阶段，免疫细胞向肾髓质间质渗透的重要性。目的2将以实验性和遗传性肾炎的形式确定渗透免疫细胞合成和释放血管紧张素转换酶的能力。 盐敏性高血压。目的3将确定在实验性和遗传性盐敏感型高血压中，肾脏中渗入的免疫细胞对肾脏血流动力学和肾脏对钠和水的处理的作用。

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.