REGULATION OF RENAL DOPAMINE-2 RECEPTORS

肾多巴胺-2 受体的调节

• 批准号: 2143338
• 负责人: DENNIS P HEALY
• 金额: $ 13.74万
• 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/2143338
• 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几种因素的精细调节 荷尔蒙、神经和自我调节过程。未能排出过量的尿液 钠被认为是导致癌症发生的原因之一。 高血压。最近的研究表明多巴胺(DA)可能是一种 肾内利钠激素。此外，肾内活动不足 多巴胺能系统被认为与这种疾病的发生有关。 或维持人类原发性高血压。我们最近报道了 肾脏内髓集合管(IMCD)细胞表达一种新的 DA2样受体(DA2K)，其刺激增加前列腺素E_2 (PGE2)合成。DA2k受体在IMCD细胞上的定位 提示内髓可能是外源性或 肾内形成的DA可以影响水的排泄和 电解液。这里提出的实验是为了刻画 其药理特性及其可能的生理作用 DA2K受体在内髓的作用，特别是 钠对延髓内侧DA2K受体系统表达的影响我们 将同时利用体外和整体动物模型。我们建议 确定：1)DA2K受体介导PGE2升高的机制 在IMCD细胞中产生，即DA2K受体直接偶联到 磷脂酶A2通过G蛋白或磷脂酶的间接激活 A2通过细胞内钙的动员；2)DA是否抑制 血管加压素通过DA2K激活IMCD细胞的腺苷环化酶活性 受体；3)DA2K受体介导的反应是否在 4)DA2K受体系统是否被划分为 IMCD细胞的顶端或基底侧细胞膜；5)对 高渗对IMCD细胞DA2K受体结合和PGE2产生的影响； 6)DA2K受体激活是否改变IMCD的钠重吸收 细胞；7)钠摄入是否改变大鼠脑内DA2K受体的表达 肾脏内髓；8)DA2K受体是否在内侧表达 DOCA-盐性高血压大鼠延髓改变；9)DA2K受体 Dahl盐敏感症患者内髓表达改变 以及10)内髓DA2K受体是否 在其他物种中表达，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受体在调节水和电解质动态平衡中的作用 此外，这些实验应该确定DA2K受体是否 内髓中的系统受钠调节，如果是这样，是否有 这一制度规则的变化有助于 钠依赖型高血压。

项目成果

Cloning of the porcine D1A dopamine receptor gene expressed in renal epithelial LLC-PK1 cells.

肾上皮 LLC-PK1 细胞中表达的猪 D1A 多巴胺受体基因的克隆。

• DOI: 10.1152/ajprenal.1995.268.3.f423
• 发表时间: 1995
• 期刊: The American journal of physiology.
• 作者: Grenader,AC;O'Rourke,DA;Healy,DP
• 通讯作者: Healy,DP

Cloning of the dopamine-1A (D1A) receptor gene expressed in porcine renal epithelial cells.

猪肾上皮细胞中表达的多巴胺-1A (D1A) 受体基因的克隆。

• DOI: 10.1291/hypres.18.supplementi_s11
• 发表时间: 1995
• 期刊: Hypertension research : official journal of the Japanese Society of Hypertension
• 作者: Healy,DP;O'Rourke,DA;Grenader,AC
• 通讯作者: Grenader,AC