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拨款，中心主题是“由上皮细胞、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，通过改变肾脏血流动力学、改变NaCI重吸收和调节细胞间的串扰，在调节肾脏排泄盐分和水分从而调节血压方面发挥重要作用。”需要验证的中心假设是，肾脏通过整合PRCH和抗高血压药物对肾单位运输、肾脏血管阻力、肾脏激素释放以及上皮细胞和血管细胞之间的相互作用来调节血压。降压药和降压药整合过程和/或作用的缺陷会导致肾功能障碍、盐滞留和高血压。这一假设将在四个项目中得到验证，这四个项目将为我们理解肾脏如何调节血压开辟新的天地。项目1将研究粗大上肢的管腔血流增加是否刺激一氧化氮合成酶3产生一氧化氮(NO)，所涉及的信号级联反应，流动诱导的NO对NaCI重吸收的影响，以及对流动刺激的NO产生的缺陷反应是否增强盐渍滞留并促进盐敏性高血压。项目2将测试NO是否通过激活cGMP刺激的磷酸二酯酶2(PDE2)，减少cAMP，从而减少Na/K/2CI共转运来抑制厚重上肢NaCI的重吸收。它还将在Dahl盐敏感大鼠身上测试NO诱导的抑制NACI重吸收和高血压的减少是否由PDE2活性降低和磷酸二酯酶5促进cGMP降解引起。项目3将测试致密斑内的血红素加氧酶是否产生一氧化碳(CO)和胆绿素，这两种物质协同作用并以自分泌方式抑制小管神经节反馈。它还将测试CO是否通过刺激cGMP起作用，cGMP抑制Na/K/2CI共转运，并阻止ATP释放，而胆绿素通过减少超氧化物歧化作用，从而增加NO。项目4将测试细胞外钙的增加是否通过激活肾小球旁细胞上的钙感应受体来抑制肾素的释放，而肾小球旁细胞上的钙感应受体通过抑制腺苷环化酶-V和刺激磷酸二酯酶1来增加细胞内钙和减少cAMP的产生。这些研究将在亚细胞、细胞和隔离组织水平上进行，并在体内使用急性和慢性模型以及基因操作的小鼠进行。这四个项目将得到三个核心单位(行政、分子生物学和分析以及成像)的支持，它们将促进科学工作。该计划项目赠款将整合我们的努力、持续的合作以及共享的想法和专业知识。因此，它将加速获得肾脏调节血压的新机制的知识，并可能为抗高血压药物提供新的靶点。

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.