Dopamine, the kidney, and hypertension.
ABSTRACT There is increasing evidence that the intrarenal dopaminergic system plays an important role in the regulation of blood pressure, and defects in dopamine signaling appear to be involved in the development of hypertension. Recent experimental models have definitively demonstrated that abnormalities in intrarenal dopamine production or receptor signaling can predispose to salt-sensitive hypertension and a dysregulated renin-angiotensin system. In addition, studies in both experimental animal models and in humans with salt-sensitive hypertension implicate abnormalities in dopamine receptor regulation due to receptor desensitization resulting from increased G-protein receptor kinase 4 (GRK4) activity. Functional polymorphisms that predispose to increased basal GRK4 activity both decrease dopamine receptor activity and increase angiotensin II type 1 (AT1) receptor activity and are associated with essential hypertension in a number of different human cohorts.
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ABSTRACT: Activation of type-1 dopamine receptors (DRD1) reduces renal sodium reabsorption. In a family-based random sample of 611 untreated whites (women, 45.0%; mean age, 38.6 years), we measured blood pressure (BP). We used the endogenous lithium clearance to assess fractional sodium excretion (FE(Na)) and proximal (RNa(prox)) and distal (RNa(dist)) tubular sodium reabsorption. We investigated multivariate-adjusted associations with the DRD1 promoter (A-48G, G-94A, and C-800T) and GRK4 (Ala142Val). The frequent DRD1 haplotypes were AGC (48.2%), GGT (34.4%), and AAC (14.3%). While standardizing to mean sodium excretion (8.7 mmol/h) and adjusting for covariates and relatedness, RNa(dist) was lower in DRD1 -94GG homozygotes than -94A allele carriers (effect size, -0.94%; P=0.005) with opposite findings for FE(Na) (+0.084%; P=0.014). AGC carriers (-0.88%; P=0.012) and AAC carriers (+1.00%; P=0.004) had different RNa(dist) compared to corresponding noncarriers. Furthermore, FE(Na) was lower in AAC carriers than in noncarriers (-0.082%; P=0.019). The family-based analyses identified a significant between-family component in the variance of the renal phenotypes associated with the DRD1 polymorphisms. Transmission of the DRD1 AGC haplotype was also associated with lower systolic (-3.54 mm Hg; P=0.016) and diastolic (-2.80 mm Hg; P=0.0064) BPs without significant between-family variance component. Plasma renin activity and urinary aldosterone excretion were not associated with DRD1 variation. The GRK4 Ala142Val polymorphism did not contribute to the phenotypes under study. In conclusion, renal sodium handling and BP were associated with genetic variation in the DRD1 promoter. The between-family variance component excluded population stratification for BP, but not for the renal phenotypes.Hypertension 07/2008; 51(6):1643-50. · 6.87 Impact Factor
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ABSTRACT: The Na(+)/phosphate cotransporter NaPi-IIa (SLC34A1) is the major transporter mediating the reabsorption of P(i) in the proximal tubule. Expression and activity of NaPi-IIa is regulated by several factors, including parathyroid hormone, dopamine, metabolic acidosis, and dietary P(i) intake. Dopamine induces natriuresis and phosphaturia in vivo, and its actions on several Na(+)-transporting systems such as NHE3 and Na(+)-K(+)-ATPase have been investigated in detail. Using freshly isolated mouse kidney slices, perfused proximal tubules, and cultured renal epithelial cells, we examined the acute effects of dopamine on NaPi-IIa expression and localization. Incubation of isolated kidney slices with the selective D(1)-like receptor agonists fenoldopam (10 microM) and SKF-38393 (10 microM) for 1 h induced NaPi-IIa internalization and reduced expression of NaPi-IIa in the brush border membrane (BBM). The D(2)-like selective agonist quinpirole (1 microM) had no effect. The D(1) and D(2) agonists did not affect the renal Na(+)/sulfate cotransporter NaSi in the BBM of the proximal tubule. Studies with isolated perfused proximal tubules demonstrated that activation of luminal, but not basolateral, D(1)-like receptors caused NaPi-IIa internalization. In kidney slices, inhibition of PKC (1 microM chelerythrine) or ERK1/2 (20 microM PD-098089) pathways did not prevent the fenoldopam-induced internalization. Inhibition with the PKA blocker H-89 (10 microM) abolished the effect of fenoldopam. Immunoblot demonstrated a reduction of NaPi-IIa protein in BBMs from kidney slices treated with fenoldopam. Incubation of opossum kidney cells transfected with NaPi-IIa-green fluorescent protein chimera shifted fluorescence from the apical membrane to an intracellular pool. In summary, dopamine induces internalization of NaPi-IIa by activation of luminal D(1)-like receptors, an effect that is mediated by PKA.American journal of physiology. Renal physiology 05/2005; 288(4):F740-7. · 3.61 Impact Factor
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ABSTRACT: Hypertension and salt sensitivity of blood pressure are two conditions the etiologies of which are still elusive because of the complex influences of genes, environment, and behavior. Recent understanding of the molecular mechanisms that govern sodium homeostasis is shedding new light on how genes, their protein products, and interacting metabolic pathways contribute to disease. Sodium transport is increased in the proximal tubule and thick ascending limb of Henle of the kidney in human essential hypertension. This Review focuses on the counter-regulation between the dopaminergic and renin-angiotensin systems in the renal proximal tubule, which is the site of about 70% of total renal sodium reabsorption. The inhibitory effect of dopamine is most evident under conditions of moderate sodium excess, whereas the stimulatory effect of angiotensin II is most evident under conditions of sodium deficit. Dopamine and angiotensin II exert their actions via G protein-coupled receptors, which are in turn regulated by G protein-coupled receptor kinases (GRKs). Polymorphisms that lead to aberrant action of GRKs cause a number of conditions, including hypertension and salt sensitivity. Polymorphisms in one particular member of this family-GRK4-have been shown to cause hyperphosphorylation, desensitization and internalization of a member of the dopamine receptor family, the dopamine 1 receptor, while increasing the expression of a key receptor of the renin-angiotensin system, the angiotensin II type 1 receptor. Novel diagnostic and therapeutic approaches for identifying at-risk subjects, followed by selective treatment of hypertension and salt sensitivity, might center on restoring normal receptor function through blocking the effects of GRK4 polymorphisms.Nature Clinical Practice Nephrology 12/2006; 2(11):637-50. · 6.08 Impact Factor