Essential hypertension has a heritability as high as 30 -50%, but its genetic cause(s) has not been determined despite intensive investigation. The renal dopaminergic system exerts a pivotal role in maintaining fluid and electrolyte balance and participates in the pathogenesis of genetic hypertension. In genetic hypertension, the ability of dopamine and D1-like agonists to increase urinary sodium excretion is impaired. A defective coupling between the D1 dopamine receptor and the G protein͞effector enzyme complex in the proximal tubule of the kidney is the cause of the impaired renal dopaminergic action in genetic rodent and human essential hypertension. We now report that, in human essential hypertension, single nucleotide polymorphisms of a G protein-coupled receptor kinase, GRK4␥, increase G protein-coupled receptor kinase (GRK) activity and cause the serine phosphorylation and uncoupling of the D1 receptor from its G protein͞effector enzyme complex in the renal proximal tubule and in transfected Chinese hamster ovary cells. Moreover, expressing GRK4␥A142V but not the wild-type gene in transgenic mice produces hypertension and impairs the diuretic and natriuretic but not the hypotensive effects of D1-like agonist stimulation. These findings provide a mechanism for the D1 receptor coupling defect in the kidney and may explain the inability of the kidney to properly excrete sodium in genetic hypertension.L ong-term regulation of blood pressure is vested in the organ responsible for the control of body fluid volume, the kidney (1, 2). Dopamine facilitates the antihypertensive function of the kidney because it is both vasodilatory and natriuretic (3). Dopamine (produced by renal proximal tubules) via D 1 -like receptors is responsible for over 50% of incremental sodium excretion when sodium intake is increased (3-6). The paracrine͞ autocrine dopaminergic regulation of sodium excretion is mediated by tubular but not by hemodynamic mechanisms (6). The ability of dopamine and D 1 -like agonists to decrease renal proximal tubular sodium reabsorption is impaired in genetic rodent hypertension and human essential hypertension (3,5,(7)(8)(9)(10)(11)(12)(13)(14)(15). Indeed, the aberrant D 1 -like receptor function in the kidney precedes and cosegregates with high blood pressure in spontaneously hypertensive rats. In addition, disruption of the D 1 receptor in mice produces hypertension (12, 13). The pivotal role of dopamine in the excretion of sodium after increased sodium intake has led to the hypothesis that an aberrant renal dopaminergic system is important in the pathogenesis of some forms of genetic hypertension (3,5,(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Several mechanisms potentially responsible for the failure of endogenous renal dopamine to engender a natriuretic effect in genetic hypertension have been investigated and ruled out, including decreased renal dopamine production and receptor expression, aberrant nephron segment distribution of dopamine receptors, defective effector enzymes (adenylyl cyclase or...

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Since dopamine receptors are important in the regulation of renal and cardiovascular function, we studied the cardiovascular consequences of the disruption of the D 3 receptor, a member of the family of D 2 -like receptors, expressed in renal proximal tubules and juxtaglomerular cells. Systolic and diastolic blood pressures were higher ( ‫ف‬ 20 mmHg) in heterozygous and homozygous than in wild-type mice. An acute saline load increased urine flow rate and sodium excretion to a similar extent in wild-type and heterozygous mice but the increase was attenuated in homozygous mice. Renal renin activity was much greater in homozygous than in wild-type mice; values for heterozygous mice were intermediate. Blockade of angiotensin II subtype-1 receptors decreased systolic blood pressure for a longer duration in mutant than in wild-type mice. Thus, disruption of the D 3 receptor increases renal renin production and produces renal sodium retention and renin-dependent hypertension. ( J .

dopamine receptor regulation of reactive oxygen species production, NADPH oxidase, and blood pressure. Am J Physiol Regul Integr Comp Physiol 290: R96 -R104, 2006; doi:10.1152/ajpregu.00434.2005.-Activation of D1-like receptors (D 1 and/or D5) induces antioxidant responses; however, the mechanism(s) involved in their antioxidant actions are not known. We hypothesized that stimulation of the D 5 receptor inhibits NADPH oxidase activity, and thus the production of reactive oxygen species (ROS). We investigated this issue in D 5 receptor-deficient (D5Ϫ/Ϫ) and wild-type (D 5ϩ/ϩ) mice. NADPH oxidase protein expression (gp91 phox , p47 phox , and Nox 4) and activity in kidney and brain, as well as plasma thiobarbituric acid-reactive substances (TBARS) were higher in D 5Ϫ/Ϫ than in D5ϩ/ϩ mice. Furthermore, apocynin, an NADPH oxidase inhibitor, normalized blood pressure, renal NADPH oxidase activity, and plasma TBARS in D 5Ϫ/Ϫ mice. In HEK-293 cells that heterologously expressed human D 5 receptor, its agonist fenoldopam decreased NADPH oxidase activity, expression of one of its subunits (gp91 phox ), and ROS production. The inhibitory effect of the D 5 receptor activation on NADPH oxidase activity was independent of cAMP/PKA but was partially dependent on phospholipase D2. The ability of D5 receptor stimulation to decrease ROS production may explain, in part, the antihypertensive action of D 5 receptor activation. hypertension DURING THE PAST DECADE, DOPAMINE has been shown as an important regulator of blood pressure, sodium balance, and renal and adrenal function through an independent peripheral dopaminergic system (32). Dopamine exerts its actions via two families of cell surface receptors that belong to the superfamily of G protein-coupled receptors. D 1 -like receptors (D 1 and D 5 ) stimulate adenylyl cyclases, while D 2 -like receptors (D 2 , D 3 , and D 4 ) inhibit adenylyl cyclases (32,45). Abnormal signaling of D 1 -like receptors has been shown to be involved in rodent models of genetic hypertension and in humans with essential hypertension (7,10,17,28,32,55). However, the precise D 1 -like receptor involved remains to be determined. There is an abnormal renal D 1 function in hypertension, which is caused by activated variants of the G protein-coupled receptor kinase type 4 (16, 32). The D 5 locus is not linked to hypertension in Dahl salt-sensitive rats (22), and mutations of the D 5 are not found in spontaneously hypertensive rats (3). However, the locus of the human D 5 (hD 5 ), 4p15.1-16

Abstract-The ability of the dopamine-1 (D 1 )-like receptor to stimulate adenylyl cyclase (AC) and phospholipase C (PLC), inhibit sodium transport in the renal proximal tubule (RPT), and produce natriuresis is attenuated in several rat models of hypertension. Since the inhibitory effect of D 1 -like receptors on RPT sodium transport is also reduced in some patients with essential hypertension, we measured D 1 -like receptor coupling to AC and PLC in cultures of human RPT cells from normotensive (NT) and hypertensive (HT) subjects. Basal cAMP concentrations were the same in NT (nϭ6) and HT (nϭ4). However, the D 1 -like receptor agonist fenoldopam increased cAMP production to a greater extent in NT (maximum responseϭ67Ϯ1%) than in HT (maximum responseϭ17Ϯ5%), with a potency ratio of 105. Dopamine also increased cAMP production to a greater extent in NT (32Ϯ3%) than in HT (14Ϯ3%). has been shown to be a paracrine regulator of sodium transport in humans and in animals during sodium-replete conditions. 1 During states of positive sodium balance, endogenous renal dopamine facilitates sodium excretion caused by a decrease in proximal as well as distal ion and water transport. [1][2][3][4][5] The natriuretic effect of exogenous and endogenous renal dopamine (and dopamine-1 [D 1 ]-like receptor agonists) is impaired in 2 animal models of hypertension. 1 In the spontaneously hypertensive rat (SHR), the impaired natriuretic effect of dopamine and D 1 -like receptor agonists is associated with a decreased ability to inhibit Na ϩ -H ϩ exchanger 1,3,6 and Na ϩ ,K ϩ -ATPase activity in RPT. 3,7,8 The decreased ability of dopamine and D 1 -like receptor agonists to inhibit these transporters has been related to a defective dopaminergic stimulation of second messenger production by adenylyl cyclase (AC), phospholipase C (PLC), and phospholipase A 2 . 6 -10 These phenotypes may be manifestations of a defective gene important in controlling blood pressure, since the defective dopaminergic regulation of RPT transport and sodium excretion cosegregates with hypertension in rats, and disruption of one of the D 1 -like receptor genes (D 1A receptor) in mice produces hypertension. 6 A defective regulation of renal proximal tubule sodium transport by D 1 -like receptors is also present in human essential hypertension. 11,12 We hypothesized that the coupling between a D 1 -like receptor and the G protein/effector enzyme complex may also be defective in some patients with essential hypertension, similar to that seen in animal models of genetic hypertension. Therefore, we compared the effect of dopamine and fenoldopam on AC and PLC activity in human RPT in culture.

Abnormalities in dopamine production and receptor function have been described in human essential hypertension and rodent models of genetic hypertension. Under normal conditions, D 1-like receptors (D1 and D5) inhibit sodium transport in the kidney and intestine. However, in the Dahl salt-sensitive and spontaneously hypertensive rats (SHRs) and in humans with essential hypertension, the D 1-like receptor-mediated inhibition of epithelial sodium transport is impaired because of an uncoupling of the D1-like receptor from its G protein/effector complex. The uncoupling is receptor specific, organ selective, nephron-segment specific, precedes the onset of hypertension, and cosegregates with the hypertensive phenotype. The defective transduction of the renal dopaminergic signal is caused by activating variants of G protein-coupled receptor kinase type 4 (GRK4: R65L, A142V, A486V). The GRK4 locus is linked to and GRK4 gene variants are associated with human essential hypertension, especially in saltsensitive hypertensive subjects. Indeed, the presence of three or more GRK4 variants impairs the natriuretic response to dopaminergic stimulation in humans. In genetically hypertensive rats, renal inhibition of GRK4 expression ameliorates the hypertension. In mice, overexpression of GRK4 variants causes hypertension either with or without salt sensitivity according to the variant. GRK4 gene variants, by preventing the natriuretic function of the dopaminergic system and by allowing the antinatriuretic factors (e.g., angiotensin II type 1 receptor) to predominate, may be responsible for salt sensitivity. Subclasses of hypertension may occur because of additional perturbations caused by variants of other genes, the quantitative interaction of which may vary depending upon the genetic background. dopamine; D 1 dopamine receptor; G protein-coupled receptor kinase type 4 THE LONG-TERM REGULATION of blood pressure rests on renal and nonrenal mechanisms (22, 34, 41,82,85,138,143,172). The sympathetic nervous (48,91,133,198,240) and the reninangiotensin (48,62,64,81,82,122,132,143,171,205,221) systems have been shown to be important in the pathogenesis of essential hypertension, including that associated with obesity (43). However, there are several counter-regulatory pathways (39,76,135,142,169,174,184,205,219) (e.g., dopamine pathway), aberrations of which are involved in the pathogenesis of essential hypertension (3, 4, 8-18, 20, 21, 23-26, 29-33, 35, 37, 42, 44-46, 52-60, 67-70, 73-75, 77, 79, 80, 84, 86, 93-95, 97-103, 106-111, 114, 116, 118, 119, 124, 126-128, 130, 131, 136, 140, 141, 144-146, 148-156, 159-161, 163-166, 176-179, 182, 183, 186, 189, 192, 193, 195, 197, 203, 207, 209-216, 218, 224, 226-239), including that associated with obesity (16, 37,201). Dopamine can regulate blood pressure by renal and nonrenal mechanisms (e.g., intestines and central nervous system) (93,130,131,207) that also involve the renin-angiotensin system (12, 29, 46,209,211,212,226,235,236).Because the kidney is important in the long-term regu...

Since dopamine produced by the kidney is an intrarenal regulator of sodium transport, an abnormality of the dopaminergic system may be important in the pathogenesis of hypertension. In the spontaneously hypertensive rat (SHR), in spite of normal renal production of dopamine and receptor density, there is defective transduction of the D 1 receptor signal in renal proximal tubules, resulting in decreased inhibition of sodium transport (Na