Dopamine, the Kidney, and Hypertension

Division of Nephrology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Current Hypertension Reports (Impact Factor: 3.44). 03/2012; 14(2):138-43. DOI: 10.1007/s11906-012-0253-z
Source: PubMed


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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    • "Dopamine-induced activation of D 1 -and D 2 -class receptors plays a critical role in a plethora of physiological effects in the central nervous system and periphery (Baik, 2013; Beaulieu & Gainetdinov, 2011; Missale et al., 1998; Zeng et al., 2004). Hypo-and hyperstimulation of D 1 -and D 2 -class subtypes have been strongly implicated in the phenotypic expression of several neuropsychiatric and peripheral disorders, and hence, dopamine receptors represent important therapeutic targets (Beaulieu & Gainetdinov, 2011; Boyd & Mailman, 2012; Bozzi & Borrelli, 2013; Brunelin, Fecteau, & Suaud-Chagny, 2013; Cuevas, Villar, Jose, & Armando, 2013; Harris & Zhang, 2012; Huot, Johnston, Koprich, Fox, & Brotchie, 2013; Leggio et al., 2013; Missale et al., 1998; Worth, 2013; Zeng et al., 2004; Zhang, Xiong, Zhen, & Zhang, 2009). Constitutive activities of 5-HT 2C receptor, m-opioid receptor, and CB 1 receptor have been shown to modulate the mesolimbic dopamine system to potentially influence mood, reward, and food intake, respectively (see review Meye, Ramakers, & Adan, 2014). "
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    ABSTRACT: The concept of activation in the absence of agonists has been demonstrated for many GPCRs and is now solidified as one of the principal aspects of GPCR signaling. In this chapter, we review how dopamine receptors demonstrate this ability. Although difficult to prove in vivo due to the presence of endogenous dopamine and lack of subtype-selective inverse agonists and "pure" antagonists (neutral ligands), in vitro assays such as measuring intracellular cAMP, [(35)S]GTPγS binding, and [(3)H]thymidine incorporation have uncovered the constitutive activation of D1- and D2-class receptors. Nevertheless, because of limited and inconsistent findings, the existence of constitutive activity for D2-class receptors is currently not well established. Mutagenesis studies have shown that basal signaling, notably by D1-class receptors, is governed by the collective contributions of transmembrane domains and extracellular/intracellular loops, such as the third extracellular loop, the third intracellular loop, and C-terminal tail. Furthermore, constitutive activities of D1-class receptors are subjected to regulation by kinases. Among the dopamine receptor family, the D5 receptor subtype exhibits a higher basal signaling and bears resemblance to constitutively active mutant forms of GPCRs. The presence of its constitutive activity in vivo and its pathophysiological relevance, with a brief mention of other subtypes, are also discussed.
    Advances in pharmacology (San Diego, Calif.) 06/2014; 70:175-214. DOI:10.1016/B978-0-12-417197-8.00007-9
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    • "Dopamine receptors exert beneficial effects by regulating epithelial sodium transport and vascular smooth muscle tone in hypertension [7-12]. Dopamine receptors are classified into D1-like and D2-like subtypes based on their structure and pharmacology. "
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    ABSTRACT: Vascular smooth muscle cells (VSMCs) proliferation and migration, which are central in the development of vascular diseases, are regulated by numerous hormones and humoral factors. Activation of the insulin receptor stimulates VSMCs proliferation while dopamine receptors, via D1 and D3 receptors, inhibit the stimulatory effects of norepinephrine on VSMCs proliferation. We hypothesize that activation of the D4 dopamine receptor may also inhibit the proliferation and migration of VSMCs, therefore, inhibit atherosclerosis. Our current study found that insulin increased the proliferation and migration of A10 cells, an effect that was reduced in the presence of a D4 receptor agonist, PD168077. The negative effect of the D4 receptor on insulin's action may be via decreasing insulin receptor expression, because activation of the D4 receptor inhibited insulin receptor protein and mRNA expressions, indicating that the regulation occured at the transcriptional or post-transcriptional levels. To determine whether or not the inhibition of D4 receptor on insulin-mediated proliferation and migration of VSMCs has physiological significance, hyper-insulinemic Sprague-Dawley rats with balloon-injured carotid artery were treated with a D4 agonist, PD168077, (6 mg/kg/d) for 14 days. We found that PD168077 significantly inhibited neointimal formation by inhibition of VSMC proliferation. This study suggests that activation of the D4 receptor suppresses the proliferation and migration of VSMCs, therefore, inhibit atherosclerosis. The D4 receptor may be a potential therapeutic target to reduce the effects of insulin on artery remodeling.
    Cardiovascular Diabetology 06/2014; 13(1):97. DOI:10.1186/1475-2840-13-97 · 4.02 Impact Factor
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    ABSTRACT: The dopamine D-2 receptor (D2R) decreases renal reactive oxygen species (ROS) production and regulates blood pressure, in part, via positive regulation of paraoxonase 2. Sestrin2, a highly conserved antioxidant protein, regulates intracellular ROS level by regenerating hyperoxidized peroxiredoxins. We hypothesized that sestrin2 may be involved in preventing excessive renal ROS production and thus contribute to the maintenance of normal blood pressure. Moreover, the D2R may decrease ROS production, in part, through the regulation of sestrin2. Renal sestrin2 expression was lower (-62 +/- 13%) in D2R-/- than in D2R+/+ mice. Silencing D2R in human renal proximal tubule cells decreased sestrin2 expression (-53 +/- 3%) and increased hyperoxidized peroxiredoxins (2.9-fold). Stimulation of D2R in renal proximal tubule cells increased sestrin2 expression (1.6-fold), decreased hyperoxidized peroxiredoxins (-61 +/- 3%), and reduced ROS production (-31 +/- 4%). Silencing sestrin2 in renal proximal tubule cells increased hyperoxidized peroxiredoxins (2.1-fold) and ROS production (1.3-fold). Silencing sestrin2 also abolished D2R-induced decrease in peroxiredoxin hyperoxidation and partially prevented the inhibitory effect of D2R stimulation on ROS production. Silencing paraoxonase 2 increased sestrin2 ubiquitinylation (2.8-fold), decreased sestrin2 expression (-30 +/- 3%), and increased ROS production (1.3-fold), peroxiredoxin hyperoxidation (2.9-fold), and lipid peroxidation (2.3-fold), and blocked the increase in sestrin2 that occurs with D2R stimulation. In vivo renal selective silencing of sestrin2 by the renal subcapsular infusion of sestrin2 small interfering RNA (3 mu g/day; 7 days) in mice increased renal oxidative stress (1.3-fold) and blood pressure. These results suggest that the D2R, via paraoxonase 2 and sestrin2, keeps normal renal redox balance, which contributes to the maintenance of normal blood pressure.
    Free Radical Biology and Medicine 05/2012; 53(3):437-46. DOI:10.1016/j.freeradbiomed.2012.05.015 · 5.74 Impact Factor
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