Reactive Oxygen Species–Dependent Hypertension in Dopamine D ₂ Receptor–Deficient Mice

Abstract

Abstract-Dysfunction of D 2 -like receptors has been reported in essential hypertension. Disruption of D 2 R in mice (D 2 Ϫ/Ϫ ) results in high blood pressure, and several D 2 R polymorphisms are associated with decreased D 2 R expression. Because D 2 R agonists have antioxidant activity, we hypothesized that increased blood pressure in D 2 Ϫ/Ϫ is related to increased oxidative stress. D 2 Ϫ/Ϫ mice had increased urinary excretion of 8-isoprostane, a parameter of oxidative stress; increased activity of reduced nicotinamide-adenine dinucleotide phosphate oxidase in renal cortex; increased expression of the reduced nicotinamide-adenine dinucleotide phosphate oxidase subunits Nox1, Nox2, and Nox4; and decreased expression of the antioxidant enzyme heme-oxygenase-2 in the kidneys, suggesting that regulation of reactive oxygen species (ROS) production by D 2 R involves both pro-oxidant and antioxidant systems. Apocynin, a reduced nicotinamide-adenine dinucleotide phosphate oxidase inhibitor, or hemin, an inducer of heme oxigenase-1, normalized the blood pressure in D 2 Ϫ/Ϫ mice. Because D 2 Rs in the adrenal gland are implicated in aldosterone regulation, we evaluated whether alterations in aldosterone secretion contribute to ROS production in this model. Urinary aldosterone was increased in D 2 Ϫ/Ϫ mice and its response to a high-sodium diet was impaired. Spirolactone normalized the blood pressure in D 2 Ϫ/Ϫ mice and the renal expression of Nox1 and Nox4, indicating that the increased blood pressure and ROS production are, in part, mediated by impaired aldosterone regulation. However, spironolactone did not normalize the excretion of 8-isoprostane and had no effect on expression of Nox2 or heme-oxygenase-2. Our results show that the D 2 R is involved in the regulation of ROS production and that, by direct and indirect mechanisms, altered D 2 R function may result in ROS-dependent hypertension. [1][2][3] There is abundant evidence that an intact dopaminergic system is necessary to maintain normal blood pressure and that genetic hypertension is associated with alterations in dopamine production and receptor function. [1][2][3][4] In humans and rodents, some dopamine receptor genes and their regulators are in loci linked to hypertension. 3,5 The natriuretic effect of D 1 -like agonists is impaired in genetically hypertensive rats 3,4 and in human essential hypertension. 3,4 Alterations in D 2 -like receptor function have also been reported in hypertension. 1,2 Loci in chromosome 11, where the D 2 R gene is located, are linked to hypertension. 5,6 A polymorphism in exon 6 of the D 2 R gene is associated with elevated blood pressure, 7 and a TaqI polymorphism is associated with human essential hypertension. 8 Several D 2 R polymorphisms are associated with decreased D 2 R expression 9,10 and affect D 2 R mRNA stability and synthesis of the receptor. 11 The disruption of any of the dopamine receptor genes in mice produces dopamine receptor subtype-specific hypertension. 3,[12][13][14] Specifically, disruption of the D 2 R...

Lipid Peroxidation and Antioxidants in Arterial Hypertension

“…Antihypertensive effect Lack of antihypertensive effect Apocynin Prevented/attenuated mineralocorticoid-induced hypertension [86,240] Prevented/reversed glucocorticoid-induced hypertension [241] Prevented/reversed adrenocorticotropic hormone-induced hypertension [242] Prevented the development of Ang II-induced hypertension in mice [186] Prevented the development of renovascular hypertension [243] Prevented the development of hypertension induced by RAS activation [50] Reduced blood pressure in borderline and spontaneous hypertension [244] Attenuated salt-sensitive hypertension [245] Normalized blood pressure in a model of hypertension induced by disruption of dopamine D2 receptor [246] Failed to prevent the hypertension induced by chronic infusion of endothelin-1 [200] Failed to prevent hypertension in transgenic mice overexpressing renin or angiotensinogen [247,248] Failed to prevent Ang II-induced hypertension in rats [249,250] Gp91ds-tat Attenuated the blood pressure rise induced by Ang II in mice [209] Failed to attenuate salt-sensitive hypertension [251] Allopurinol Attenuated salt-sensitive hypertension [252] Prevented glucocorticoid-induced hypertension [253] Failed to prevent or attenuate mineralocorticoid-induced hypertension [254] Failed to prevent glucocorticoidinduced hypertension [255] Failed to prevent or attenuate adrenocorticotropic-induced hypertension [242] Failed to prevent the development of hypertension induced by the blockade of nitric oxide synthesis [256] Failed to prevent the progression of hypertension in young SHR [257] Oxypurinol Reduced blood pressure in SHR [258] Tempol Attenuated hypertension in SHR [201] Prevented the progression of hypertension in saltloaded SHRSP [259] Attenuated mineralocorticoid-induced hypertension [260] Failed to prevent Ang II-induced hypertension [264] Failed to attenuate hypertension induced by inhi...…”

Sestrin2 Decreases Renal Oxidative Stress, Lowers Blood Pressure, and Mediates Dopamine D 2 Receptor–Induced Inhibition of Reactive Oxygen Species Production

“…Previous studies from our laboratory have shown that disruption of Drd2 (D 2 R −/− ) increases systolic and diastolic blood pressures that are associated with increased ROS production and oxidative stress in the kidney [12, 15, 26, 27]. To determine if sestrin2 is involved in these alterations, we first measured the renal protein expression of sestrin2 in D 2 R −/− and D 2 R +/+ mice.…”

“…The original F2 hybrid mouse strain (129/SvXC57BL/6J, Oregon Health Sciences University) that contained the mutated Drd2 allele (D 2 R −/− ) was backcrossed to wild-type C57BL/6J for >5 generations and genotyped [5, 12]. Wild-type littermates (D 2 R +/+ ) were used as controls.…”

“…Increased generation of ROS in the kidney has been shown to be important in the pathogenesis of hypertension in several animal models [9–11]. Disruption of the Drd2 (D 2 R −/− ) increases ROS production and oxidative stress in the kidney and results in ROS-dependent hypertension [12]. The renal activity of NADPH oxidase and the expression of Nox-1, Nox-2, and Nox-4 are increased in D 2 R −/− [12].…”

“…Disruption of the Drd2 (D 2 R −/− ) increases ROS production and oxidative stress in the kidney and results in ROS-dependent hypertension [12]. The renal activity of NADPH oxidase and the expression of Nox-1, Nox-2, and Nox-4 are increased in D 2 R −/− [12]. We have recently shown that renal PON2, a protein that possesses antioxidant properties [13–15] and is positively regulated by D 2 R, mediates, in part, the inhibitory effect of renal D 2 R on NADPH oxidase activity and ROS production [15], and contributes to the maintenance of normal blood pressure.…”