REGULATION OF RENAL DOPAMINE-2 RECEPTORS

肾脏的钠排泄受以下因素的组合精细调节： 激素、神经元和自动调节过程。 不能排出多余的 钠被认为是导致 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 多巴胺能系统被认为有助于发展 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 DA 2样受体（DA 2K），刺激其可增加前列腺素E2 （PGE 2）合成。 DA 2k受体在IMCD细胞上的定位 提示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 的药理学特性和可能的生理作用， DA 2K受体在内部髓质，特别是，影响 钠对内髓Da 2K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）DA 2K受体介导的PGE 2增加的机制 在IMCD细胞中的产生，即DA 2K受体与 磷脂酶A2通过G蛋白，或间接激活磷脂酶 A2通过动员细胞内钙; 2）DA是否抑制 加压素通过DA 2K刺激IMCD细胞中腺苷酸环化酶活性 受体; 3）DA 2K受体介导的反应是否在 IMCD细胞; 4）DA 2K受体系统是否与IMCD细胞区室化; IMCD细胞的顶侧或基底侧细胞膜; 高渗对IMCD细胞中DA 2K受体结合和PGE 2产生的影响; 6)DA 2K受体激活是否改变IMCD中的钠重吸收 7）钠摄入是否会改变细胞中DA 2K受体的表达， 肾内髓质是否有DA 2K受体表达 DOCA-盐高血压大鼠的延髓改变; 9）DA 2K受体是否 在Dahl盐敏感的小鼠中， 高血压大鼠;和10）是否内髓质DA 2K受体是 在其他物种中表达，包括兔子，狗和人。 实验应该提供新的见解肾内的作用， DA 2K受体在水电解质稳态调节中的作用 此外，这些实验应该确定DA 2K受体是否 内髓系统受钠调节，如果是这样， 这一制度的变化有助于发展 钠依赖型高血压

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.