Blood Pressure Regulation: Novel Roles for the Kidney

血压调节：肾脏的新作用

• 批准号: 8235821
• 负责人: Pablo A. Ortiz
• 金额: $ 205.44万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8235821
• 关键词: Achievement; Acute; Adenylate Cyclase; Antihypertensive Agents; Biliverdine; Blood Pressure; Blood Vessels; Calcium-Sensing Receptors; Carbon Monoxide; Cardiac; Cells; Chronic; Collaborations; Cyclic AMP; Cyclic GMP; Dahl Hypertensive Rats; Defect; Doctor of Medicine; Doctor of Philosophy; Endocrine; Endothelial Cells; Epithelial; Excretory function; Feedback; Functional disorder; Funding; Goals; Grant; Heme; Hormones; Hypertension; Image; In Vitro; Individual; Interdisciplinary Study; Juxtaglomerular Cell; Kidney; Knowledge; Knowledge acquisition; Lead; Limb structure; Macula densa; Mediating; Microcirculation; Modeling; Molecular Biology; Mus; Nephrons; Nitric Oxide; Organ; Oxygenases; Play; Process; Production; Program Research Project Grants; Regulation; Renal function; Renin; Research; Research Activity; Research Personnel; Role; Scientist; Signal Transduction; Smooth Muscle Myocytes; Sodium Chloride; Superoxides; Testing; Thick; Tissues; Vascular resistance; Water; Work; autocrine; blood pressure regulation; extracellular; hemodynamics; human NOS3 protein; in vivo; interdisciplinary approach; interest; interstitial cell; kidney vascular structure; member; multidisciplinary; novel; paracrine; phosphodiesterase V; phosphoric diester hydrolase; programs; response; salt sensitive

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.

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“上皮细胞、血管平滑肌、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、改变氯化钠重吸收和介导细胞间的串扰，在调节肾脏盐和水排泄从而调节血压方面发挥重要作用。”要测试的中心假设是，肾脏的血压调节是通过 prch 和抗高血压药物对肾单位运输、肾血管阻力、肾激素释放以及上皮细胞和血管细胞之间的串扰的作用的整合而发生的。促高血压剂和抗高血压剂的整合过程和/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得到检验，这些项目为我们对肾脏如何调节血压的理解开辟了新的领域。项目 1 将研究增加厚升肢的管腔流量是否会刺激 NO 合酶 3 产生一氧化氮 (NO)、所涉及的信号级联、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会增强 SAIT 保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 (PDE2)、减少 cAMP 从而减少 Na/K/2CI 共转运来抑制厚升肢 NaCl 重吸收。它还将在 Dahl 盐敏感大鼠中测试 NO 诱导的 NaCl 重吸收和高血压抑制的减少是否是由于 PDE2 活性降低和磷酸二酯酶 5 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，它们以自分泌方式协同作用， 抑制肾小管球状反馈。它还将测试CO是否通过刺激cGMP发挥作用，cGMP抑制Na/K/2CI协同转运，并阻止ATP释放，胆绿素通过减少超氧化物发挥作用，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旁细胞上的 Ca 感应受体来抑制肾素释放，从而增加细胞内 Ca 并通过抑制腺苷酸环化酶-V 和刺激磷酸二酯酶 1 减少 cAMP 产生。这些研究将在亚细胞、细胞和分离组织水平上进行体外，并使用急性和慢性模型以及遗传模型在体内进行。 被操纵的老鼠。这四个项目将得到三个核心单位（管理、分子生物学和分析以及成像）的支持，这将促进科学工作。该计划项目拨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，它将加速人们对肾脏调节血压的新机制的了解，并可能为抗高血压药物提供新的靶点。