REGULATION OF RENAL DOPAMINE-2 RECEPTORS

肾多巴胺-2 受体的调节

• 批准号: 3245346
• 负责人: DENNIS P HEALY
• 金额: $ 13.21万
• 依托单位: MOUNT SINAI SCHOOL OF MEDICINE OF CUNY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-02-01 至 1995-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3245346
• 关键词: G protein; angiotensin /renin /aldosterone hypertension; atrial natriuretic peptide; calcium flux; cell osmotic pressure; dietary sodium; dogs; dopamine receptor; electrolyte balance; genetic strain; homeostasis; hormone regulation /control mechanism; human tissue; hypertension; kidney pharmacology; laboratory rabbit; phospholipase A2; prostaglandin E; renal medulla; saluresis

Sodium excretion by the kidney is finely regulated by a combination of hormonal, neuronal and autoregulatory processes. Failure to excrete excess sodium has been implicated as a causal factor in the development of hypertension. Recent studies indicate that dopamine (DA) may be an intrarenal natriuretic hormone. Moreover, hypoactivity of the intrarenal dopaminergic system has been implicated as contributing to the development or maintenance of human essential hypertension. We have reported recently that kidney inner medullary collecting duct (IMCD) cells express a novel DA2-like receptor (DA2K), stimulation of which increases prostaglandin E2 (PGE2) synthesis. The localization of the DA2k receptor on IMCD cells suggests that the inner medulla may be a site at which exogenous or intrarenally-formed DA could influence the excretion of water and electrolytes. The experiments proposed here are designed to characterize the pharmacological properties and the possible physiological role of the DA2K receptor in the inner medulla and, in particular, the effects of sodium on the expression of the inner medulla Da2K receptor system. We will utilize both in vitro and whole animal models. We propose to determine: 1) the mechanism of the DA2K receptor-mediated increase in PGE2 production in IMCD cells, i.e. direct coupling of the DA2K receptor to phospholipase A2 via a G protein, or indirect activation of phospholipase A2 through mobilization of intracellular calcium; 2) whether DA inhibits vasopressin-stimulated adenylyl cyclase activity in IMCD cells via the DA2K receptor; 3) whether the DA2K receptor-mediated responses desensitize in IMCD cells; 4) whether the DA2K receptor system is compartmentalized to the apical or basolateral cell membrane of IMCD cells; 5) the effects of hyperosmolality on DA2K receptor binding and PGE2 production in IMCD cells; 6) whether DA2K receptor activation alters sodium reabsorption in IMCD cells; 7) whether sodium intake alters DA2K receptor expression in the kidney inner medulla; 8) whether DA2K receptor expression in the inner medulla is altered in DOCA-salt hypertensive rats; 9) whether DA2K receptor expression in the inner medulla is altered in Dahl salt-sensitive hypertensive rats; and 10) whether the inner medulla DA2K receptor is expressed in other species, including rabbit, dog and man. These experiments should provide new insights into the role of the intrarenal DA2K receptor in the regulation of water and electrolyte homeostasis. Furthermore, these experiments should establish whether the DA2K receptor system in the inner medulla is regulated by sodium, and if so, whether a change in the regulation of this system contributes to the development of sodium-dependent forms of hypertension.

肾脏的钠排泄受到以下因素的精细调节： 激素、神经元和自动调节过程。 无法排出多余的物质 钠被认为是导致疾病发生的一个因素 高血压。 最近的研究表明，多巴胺（DA）可能是一种 肾内利尿钠激素。 此外，肾内功能减退 多巴胺能系统被认为有助于发育 或维持人类原发性高血压。 我们最近报道过 肾脏内髓集合管（IMCD）细胞表达一种新的 DA2 样受体 (DA2K)，刺激其会增加前列腺素 E2 (PGE2) 合成。 IMCD细胞上DA2k受体的定位 表明内髓质可能是外源性或 肾内形成的DA可影响水的排泄 电解质。 这里提出的实验旨在表征 药理特性和可能的​​生理作用 内髓质中的 DA2K 受体，特别是 钠对内髓质 Da2K 受体系统表达的影响。 我们 将利用体外和整个动物模型。 我们建议 确定：1）DA2K受体介导的PGE2增加的机制 IMCD 细胞中的生产，即 DA2K 受体直接偶联 通过 G 蛋白激活磷脂酶 A2，或间接激活磷脂酶 A2 通过细胞内钙的动员； 2）DA是否抑制 IMCD 细胞中加压素通过 DA2K 刺激腺苷酸环化酶活性 受体； 3）DA2K受体介导的反应是否脱敏 IMCD细胞； 4) DA2K受体系统是否划分为 IMCD细胞的顶端或基底外侧细胞膜； 5) 的影响 IMCD 细胞中高渗透压对 DA2K 受体结合和 PGE2 产生的影响； 6) DA2K受体激活是否改变IMCD中的钠重吸收 细胞； 7）钠的摄入是否会改变DA2K受体的表达 肾内髓质； 8) DA2K受体是否在内表达 DOCA-盐高血压大鼠的髓质发生改变； 9) 是否有DA2K受体 Dahl 盐敏感的内髓质表达发生改变 高血压大鼠； 10) 内髓质 DA2K 受体是否 在其他物种中也有表达，包括兔子、狗和人。 这些 实验应该为肾内的作用提供新的见解 DA2K 受体调节水和电解质稳态。 此外，这些实验应该确定 DA2K 受体是否 内髓质系统受钠调节，如果是这样，是否存在钠调节 该系统监管的变化有助于发展 钠依赖性高血压。