Disruption of the dopamine D3 receptor gene produces renin-dependent hypertension.

Asico, Laureano D.; Ladines, Cecilia A.; Fuchs, Sara; Accili, Domenico; Carey, Robert M.; Semeraro, C.; Pocchiari, F.; Felder, Robin A.; Eisner, Gilbert M.; José, Pedro A.

doi:10.1172/jci3685

Cited by 156 publications

(189 citation statements)

References 36 publications

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“…Disruption of the D3 receptor increased renal renin production, and caused renal sodium retention as well as renin-dependent hypertension in one study. 23 The ability of dopamine to stimulate renin secretion is enhanced by a low sodium diet and blunted by a high sodium diet. 24 A defective renal dopaminergic system seems to be a major cause of renal malfunction in Dahl saltsensitive and spontaneously hypertensive rats: their kidneys produce less dopamine.…”

Section: Discussionmentioning

confidence: 99%

Renoprotective effect of a dopamine D3 receptor antagonist in experimental type II diabetes

Gross

Koch

Mühlbauer

et al. 2006

Laboratory Investigation

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Diabetic nephropathy is the leading cause of end-stage renal disease. Dopamine receptors are involved in the regulation of renal hemodynamics and may play a role in diabetes-induced hyperfiltration. To test this hypothesis, we investigated the renal effect of a dopamine D3 receptor antagonist (D3-RA) in hypertensive type II diabetic SHR/N-cp rats. Lean and obese SHR/N-cp rats were randomly assigned to D3-RA, angiotensinconverting enzyme inhibitor (ACE-i), or D3-RA þ ACE-i treatment or control conditions. Treated animals were given the D3-RA A-437203 (10 mg/kg/body weight (BW)/day) or the ACE-i trandolapril (0.3 mg/kg BW/day) or a combination of both. At 6 months following perfusion, fixed kidneys were analyzed by morphological and stereological methods. Indices of renal damage (glomerulosclerosis, glomerulosclerosis damage index (GSI), tubulointerstitial and vascular damage), glomerular geometry and functional variables such as urinary albumin excretion, glomerular filtration rate, blood pressure, blood chemistry and BW were determined. The GSI (score 0-4) was significantly higher (Po0.05) in untreated diabetic animals (1.6270.3) compared to nondiabetic controls (0.470.2) and the treatment groups (D3-RA: 0.3170.12; ACE-i: 0.2970.1; combination treatment: 0.1270.01). Urinary albumin excretion (mg/24 h) was higher in untreated diabetic controls (102719) compared to nondiabetic controls (31712) and the treatment groups (D3-RA: 44715; ACE-i: 41713; combination treatment: 1578). Mean glomerular volume was higher in untreated diabetic animals compared to nondiabetic controls and to the treatment groups. Desmin expression, a marker of podocyte damage, was elevated in untreated diabetic controls and diminished in all treatment groups. These data suggest that in a model of type II diabetes, the dopamine D3-RA had a beneficial effect on renal morphology and albuminuria, which was comparable in magnitude to that of ACE-i treatment.

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Section: Discussionmentioning

confidence: 99%

Renoprotective effect of a dopamine D3 receptor antagonist in experimental type II diabetes

Gross

Koch

Mühlbauer

et al. 2006

Laboratory Investigation

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“…The mice were anesthetized with pentobarbital (50 mg͞kg i.p. ), placed on a heated board to maintain body temperature at 37°C, and tracheotomized (33). Catheters were inserted into the femoral vessels for fluid administration, blood drawing, and blood pressure monitoring.…”

Section: Methodsmentioning

confidence: 99%

G protein-coupled receptor kinase 4 gene variants in human essential hypertension

Felder

Sanada

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

250

419

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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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“…Abnormalities of signaling by GPCRs have been associated with several diseases, such as hypertension [12,13], precocious puberty [14,15], hyperthyroidism [16], nephrogenic diabetes insipidus [14,17], cancer [18] and blindness [19,20]. The sequencing of the human genome [21,22,23] has revealed several hundred members of GPCRs including orphan GPCRs with yet unknown ligands, indicating the future therapeutic potential of targeting the GPCR superfamily [8].…”

Section: G-protein-coupled Receptors (Gpcrs)mentioning

confidence: 99%

Crystal structure of the ligand-free G-protein-coupled receptor opsin

Park

Scheerer

Hofmann

et al. 2008

Nature

858

925

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Compared with the known structure of inactive rhodopsin, opsin displays prominent structural changes in the conserved E(D)RY and NPxxY(x) 5,6 F regions and TM5-TM7. At the cytoplasmic side, TM6 is tilted outwards by 6-7 Å, whereas the helix structure of TM5 is more elongated and close to TM6. These structural changes, of which some are attributed to an active GPCR state, reorganize the empty retinal binding pocket to disclose two openings for exit and entry of retinal. The opsin structure thus sheds new light on binding of hydrophobic ligands to GPCRs, GPCR activation and signal transfer to the G protein.

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Disruption of the dopamine D3 receptor gene produces renin-dependent hypertension.

Cited by 156 publications

References 36 publications

Renoprotective effect of a dopamine D3 receptor antagonist in experimental type II diabetes

Renoprotective effect of a dopamine D3 receptor antagonist in experimental type II diabetes

G protein-coupled receptor kinase 4 gene variants in human essential hypertension

Crystal structure of the ligand-free G-protein-coupled receptor opsin

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