Blood Pressure Regulation: Novel Roles for the Kidney

描述（由申请人提供）： 这是一项修订后的计划项目资助，中心主题是“上皮细胞、血管平滑肌细胞、内皮细胞和间质细胞产生的内分泌、旁分泌和自分泌因子通过改变肾脏血液动力学、改变NaCl重吸收和介导细胞间的串扰，在调节肾脏的盐和水排泄以及血压方面发挥重要作用。“有待检验的中心假设是，肾脏对血压的调节是通过prch和抗高血压药物对肾单位转运、肾血管阻力、肾激素释放以及上皮细胞和血管细胞之间的相互作用的综合作用而发生的。促高血压药物和抗高血压药物的整合过程和/或作用的缺陷导致肾功能障碍、盐潴留和高血压。这一假设将在四个项目中进行测试，这些项目在我们对肾脏如何调节血压的理解中开辟了新的天地。项目1将研究增加粗升支中的管腔流量是否刺激NO合成酶3产生一氧化氮（NO），涉及的信号级联，流量诱导的NO对NaCl重吸收的影响，以及对流量刺激的NO产生的缺陷反应是否增强盐潴留并促进盐敏感性高血压。项目2将测试NO是否通过激活cGMP刺激的磷酸二酯酶2（PDE 2），减少cAMP，从而减少Na/K/2CI共转运来抑制厚的上行肢体NaCl重吸收。还将在Dahl盐敏感大鼠中测试NO诱导的NaCl重吸收抑制和高血压的降低是否是由磷酸二酯酶5降低的PDE 2活性和增强的cGMP降解引起的。项目3将测试致密斑中的血红素加氧酶是否产生一氧化碳（CO）和胆绿素，它们协同作用并以自分泌方式抑制微管球蛋白反馈。它还将测试CO是否通过刺激cGMP（其抑制Na/K/2CI共转运）起作用，并阻断ATP释放，胆绿素是否通过减少超氧化物起作用，从而增加NO。项目4将测试增加的细胞外Ca是否通过激活肾小球细胞上的Ca敏感受体来抑制肾素释放，所述Ca敏感受体通过抑制腺苷酸环化酶-V和刺激磷酸二酯酶1来增加细胞内Ca并减少cAMP产生。这些研究将在亚细胞、细胞和分离组织水平进行体外研究，并使用急性和慢性模型以及遗传操作小鼠进行体内研究。这四个项目将由三个核心单位（行政，分子生物学和分析，以及成像）支持，这将促进科学工作。该计划项目赠款将提供我们的努力，持续合作和共享的想法和专业知识的整合。因此，它将加速获得知识的新机制，肾脏调节血压，并可能提供新的抗高血压药物的目标。

DESCRIPTION (provided by applicant): This is a revised Program Project Grant, the central theme is that "endocrine, paracrine and autoerine factors produced by the epithelial, vascular smooth muscle, endothelial and interstitial cells play an important role in regulating salt and water excretion by the kidney, and thus blood pressure, by altering renal hempdynamics, changing NaCI reabsorption and mediating cross-talk between cells." The central hypothesis to be tested is that blood pressure regulation by the kidney occurs via integration of the actions of prch and anti-hypertensive agents on nephron transport, renal vascular resistance, release of renal hormones and cross-talk between epithelial and vascular cells. Defects in the integration process and/or actions of pro- and anti-hypertensive agents lead to renal dysfunction, salt retention and hypertension. This hypothesis will be tested in four projects that break new ground in our understanding of how the kidney regulates blood pressure. Project 1 will study whether increasing luminal flow in the thick ascending limb stimulates nitric oxide (NO) production by NO synthase 3, the signaling cascades involved, the effects of flow-induced NO on NaCI reabsorption, and whether a defective response to flow-stimulated NO production enhances sait retention and promotes salt-sensitive hypertension. Project 2 will test whether NO inhibits thick ascending limb NaCI reabsorption by activating cGMP-stimulated phosphodiesterase 2 (PDE2), reducing cAMP, and thus decreasing Na/K/2CI cotransport. It will also test in Dahl salt-sensitive rats whether a reduction in NOinduced inhibition of NaCI reabsorption and hypertension is caused by diminished PDE2 activity and enhanced cGMP degradation by phosphodiesterase 5. Project 3 will test whether heme oxygenases in the macula densa produce carbon monoxide (CO) and biliverdin, which act synergistically and in an autocrine manner to inhibit tubuloglomeailar feedback. It will also test whether CO acts by stimulating cGMP which inhibits Na/K/2CI cotransport, and blocks ATP release and biliverdin acts by decreasing superoxide, thereby increasing NO. Project 4 will test whether increased extracellular Ca inhibits renin release by activating Ca sensing receptors on juxtaglomerular cells which increases intracellular Ca and reduces cAMP production by inhibiting adenylyl cyclase-V and stimulating phosphodiesterase 1. These studies will be performed in vitro at the subcellular, cellular, and isolated tissue levels and in vivo using both acute and chronic models, and genetically manipulated mice. The four projects will be supported by three core units (Administrative, Molecular Biology and Analytical, and Imaging) that will facilitate the scientific effort. The Program Project Grant will provide integration of our efforts, continued collaboration and shared ideas and expertise. Thus it will accelerate acquisition of knowledge of the novel mechanisms by which the kidney regulates blood pressure, and may provide new targets for anti-hypertensive drugs.