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.
| Grenader, A C; O'Rourke, D A; Healy, D P (1995) Cloning of the porcine D1A dopamine receptor gene expressed in renal epithelial LLC-PK1 cells. Am J Physiol 268:F423-34 |
| Healy, D P; Ye, M Q; Troyanovskaya, M (1995) Localization of angiotensin II type 1 receptor subtype mRNA in rat kidney. Am J Physiol 268:F220-6 |
| Healy, D P; O'Rourke, D A; Grenader, A C (1995) Cloning of the dopamine-1A (D1A) receptor gene expressed in porcine renal epithelial cells. Hypertens Res 18 Suppl 1:S11-7 |
