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ABSTRACT: Abnormalities in renal angiotensin type 1 receptor (AT1R), D1 dopamine receptor (D1R) and G protein-coupled receptor kinase 4 (GRK4) are present in polygenic hypertension. Selective renal reduction of AT1R expression by intrarenal cortical infusion of antisense oligodeoxynucleotides (As-Odns) in conscious, uninephrectomized, sodium-loaded rats decreases proteinuria, normalizes the glomerular sclerosis index (GSI), increases the sodium excretion (UNaV), and modestly increases blood pressure (BP) in spontaneously hypertensive rats (SHR) but not in normotensive Wistar-Kyoto rats (WKY). In contrast, selective renal reduction of GRK4 expression by infusion of GRK4 As-Odns increases UnaV, attenuates the increase in arterial BP with age, and modestly decreases protein excretion in SHR, but not in WKY. In this study, we report that intrarenal cortical infusion of both GRK4 and AT1R As-Odns decreased BP and increased UNaV in SHR; these effects were also noted in WKY to a lesser extent. Infusion of SHR with this combination of As-Odns resulted in a decrease in proteinuria and improvement of GSI similar to those by AT1R As-Odn only. In contrast to the increased circulating angiotensin II and aldosterone levels induced by AT1R As-Odn alone, the combination of As-Odns decreased both, contributing to greater natriuresis and amelioration of hypertension than by GRK4 or AT1R As-Odn only. Our results indicate an interaction between GRK4-regulated receptors and the renin-angiotensin system in the regulation of renal function and BP.
Hypertension Research 08/2008; 31(7):1455-64. · 2.58 Impact Factor
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Hironobu Sanada,
Junichi Yatabe, Sanae Midorikawa,
Tetsuo Katoh,
Shigeatsu Hashimoto,
Tsuyoshi Watanabe,
Jing Xu,
Yingjin Luo,
Xiaoyan Wang,
Chunyu Zeng,
Ines Armando,
Robin A Felder,
Pedro A Jose
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ABSTRACT: Abnormalities in D1 dopamine receptor function in the kidney are present in some types of human essential and rodent genetic hypertension. We hypothesize that increased activity of G protein-coupled receptor kinase type 4 (GRK4) causes the impaired renal D1 receptor function in hypertension. We measured renal GRK4 and D1 and serine-phosphorylated D1 receptors and determined the effect of decreasing renal GRK4 protein by the chronic renal cortical interstitial infusion (4 weeks) of GRK4 antisense oligodeoxynucleotides (As-Odns) in conscious- uninephrectomized spontaneously hypertensive rats (SHRs) and their normotensive controls, Wistar-Kyoto (WKY) rats. Basal GRK4 expression and serine-phosphorylated D1 receptors were &90% higher in SHRs than in WKY rats and were decreased to a greater extent in SHRs than in WKY rats with GRK4 As-Odns treatment. Basal renal D1 receptor protein was similar in both rat strains. GRK4 As-Odns, but not scrambled oligodeoxynucleotides, increased sodium excretion and urine volume, attenuated the increase in arterial blood pressure with age, and decreased protein excretion in SHRs, effects that were not observed in WKY rats. These studies provide direct evidence of a crucial role of renal GRK4 in the D1 receptor control of sodium excretion and blood pressure in genetic hypertension.
Hypertension 06/2006; 47(6):1131-9. · 6.21 Impact Factor
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Hironobu Sanada,
Junichi Yatabe, Sanae Midorikawa,
Shigeatsu Hashimoto,
Tsuyoshi Watanabe,
Jason H Moore,
Marylyn D Ritchie,
Scott M Williams,
John C Pezzullo,
Midori Sasaki,
Gilbert M Eisner,
Pedro A Jose,
Robin A Felder
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ABSTRACT: Salt-sensitive (SS) hypertension affects >30 million Americans and is often associated with low plasma renin activity. We tested the diagnostic validity of several candidate genes for SS and low-renin hypertension.
In Japanese patients with newly diagnosed, untreated hypertension (n = 184), we studied polymorphisms in 10 genes, including G protein-coupled receptor kinase type 4 (GRK4), some variations of which are associated with hypertension and impair D1 receptor (D1R)-inhibited renal sodium transport. We used the multifactor dimensionality reduction method to determine the genotype associated with salt sensitivity (> or =10% increase in blood pressure with high sodium intake) or low renin. To determine whether the GRK4 genotype is associated with impaired D1R function, we tested the natriuretic effect of docarpamine, a dopamine prodrug, in normotensive individuals with or without GRK4 polymorphisms (n = 18).
A genetic model based on GRK4 R65L, GRK4 A142V, and GRK4 A486V was 94.4% predictive of SS hypertension, whereas the single-locus model with only GRK4 A142V was 78.4% predictive, and a 2-locus model of GRK4 A142V and CYP11B2 C-344T was 77.8% predictive of low-renin hypertension. Sodium excretion was inversely related to the number of GRK4 variants in hypertensive persons, and the natriuretic response to dopaminergic stimulation was impaired in normotensive persons having > or =3 GRK4 gene variants.
GRK4 gene variants are associated with SS and low-renin hypertension. However, the genetic model predicting SS hypertension is different from the model for low renin, suggesting genetic differences in these 2 phenotypes. Like low-renin testing, screening for GRK4 variants may be a useful diagnostic adjunct for detection of SS hypertension.
Clinical Chemistry 04/2006; 52(3):352-60. · 7.91 Impact Factor
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ABSTRACT: Hypertension is a major risk factor for atherosclerotic cardiovascular disease. Selectins, cell-surface adhesion molecules involved in leukocyte rolling and attachment to the vascular endothelium, play a role in the initiation of atherosclerosis. We investigated whether or not serum levels of soluble adhesion molecules are elevated in patients with essential hypertension (EH) and examined whether antihypertensive therapy lowers such levels. Twenty-one patients who had untreated mild to moderate EH without diabetes mellitus, hyperlipidemia, or obesity were recruited at a clinic for hypertensive patients. Blood pressure was measured, and the serum levels of soluble E-selectin, P-selectin, L-selectin, intercellular adhesion molecule 1 (ICAM-1), and vascular-cell adhesion molecule 1 (VCAM-1) were determined by enzyme-linked immunosorbent assays before and after 12, 24, and 53 weeks of antihypertensive treatment with benidipine, a long-acting calcium channel blocker, given at a dose of 6 mg/day for 53 weeks. As a control, 21 age- and sex-matched patients without hypertension were studied. Serum E- and P-selectin levels were significantly higher in the subjects with EH than in the controls (p < 0.01). There were no differences in serum levels of soluble L-selectin, VCAM-1, or ICAM-1 levels between the patients with EH and the controls. Treatment with benidipine decreased the elevated blood pressure over a 53-week study period (mean blood pressure: 119.8 +/- 6.5 mmHg at baseline, 101.0 +/- 5.9 mmHg at 12 weeks, 98.6 +/- 7.3 mmHg at 24 weeks, and 93.9 +/- 5.5 mmHg at 53 weeks). Serum levels of soluble E- and P-selectin decreased after the initiation of benidipine treatment and correlated with diastolic blood pressure. Serum levels of soluble L-selectin, VCAM-1, and ICAM-1 did not change significantly during the period of benidipine treatment. Benidipine treatment reduced the content of P-selectin in the platelets from patients with EH, as determined by Western blot analysis. In conclusion, decreased blood pressure may reduce the rate of progression of atherosclerosis by affecting the expression of E- and P-selectin in the endothelium, the platelets, or both. Benidipine may be protective against vascular damage in people with hypertension, not only by lowering blood pressure, but also by inhibiting the expression of selectins.
Hypertension Research 11/2005; 28(11):871-8. · 2.58 Impact Factor
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Minoru Yoneda,
Hironobu Sanada,
Junichi Yatabe, Sanae Midorikawa,
Shigeatsu Hashimoto,
Midori Sasaki,
Tetsuo Katoh,
Tsuyoshi Watanabe,
Peter M Andrews,
Pedro A Jose,
Robin A Felder
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ABSTRACT: The effect of selectively decreasing renal angiotensin II type 1 (AT1) receptor expression on renal function and blood pressure has not been determined. Therefore, we studied the consequences of selective renal inhibition of AT1 receptor expression in normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) in vivo. Vehicle, AT1 receptor antisense oligodeoxynucleotides (AS-ODN), or scrambled oligodeoxynucleotides were infused chronically into the cortex of the remaining kidney of conscious, uninephrectomized WKY and SHR on a 4% NaCl intake. Basal renal cortical membrane AT1 receptor protein was greater in SHR than in WKY. In WKY and SHR, AS-ODN decreased renal but not cardiac AT1 receptors. AT1 receptor AS-ODN treatment increased plasma renin activity to a greater extent in WKY than in SHR. However, plasma angiotensin II and aldosterone were increased by AS-ODN to a similar degree in both rat strains. In SHR, sodium excretion was increased and sodium balance was decreased by AS-ODN but had only a transient ameliorating effect on blood pressure. Urinary protein and glomerular sclerosis were markedly reduced by AS-ODN-treated SHR. In WKY, AS-ODN had no effect on sodium excretion, blood pressure, or renal histology but also modestly decreased proteinuria. The major consequence of decreasing renal AT1 receptor protein in the SHR is a decrease in proteinuria, probably as a result of the amelioration in glomerular pathology but independent of systemic blood pressure and circulating angiotensin II levels.
Hypertension 08/2005; 46(1):58-65. · 6.21 Impact Factor
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ABSTRACT: Diabetic nephropathy is a common complication in diabetes mellitus (DM). Thiazolidinedione (TZD) is thought to ameliorate diabetic nephropathy, however, the mechanism has not been elucidated. We hypothesized that VEGF participates in the pathogenesis of diabetic nephropathy and that TZD may be beneficial for the treatment of diabetic nephropathy through its effect on VEGF. Increased VEGF expression was demonstrated in the glomeruli of DM rats and rat mesangial cells (RMC) incubated with high medium glucose. It was also demonstrated that VEGF promoted mesangial cell proliferation, which was inhibited by TZD. It was shown that a rapid fall and rise of ambient glucose concentration induces more VEGF production and cell proliferation in RMC than in cells with continuously high glucose medium, which was also inhibited by TZD. Prostaglandin J2 and protein C kinase inhibitors significantly inhibited [3H]thymidine incorporation in RMC incubated with VEGF, which was inhibited by TZD. These findings indicate that a rapid change of glucose concentration promotes RMC proliferation by the increased production of VEGF. TZD has an inhibitory action through, at least in part, PPAR-gamma.
Biochemical and Biophysical Research Communications 05/2004; 317(1):24-9. · 2.48 Impact Factor
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ABSTRACT: A 23-year-old female with polycystic ovary syndrome (PCOS) and a growth-hormone (GH)-producing pituitary adenoma is described. A reduction in the elevated GH levels to normal levels following the administration of dopaminergic agents decreased plasma insulin-like growth factor (IGF)-1 and ovarian dysfunction. Menstrual cycles were therefore restored and the number of ovarian cysts reduced, suggesting that insulin and/or IGF-1, stimulators of theca cell proliferation, may be pathogenetic factors in PCOS.
Hormone Research 02/2003; 59(3):149-55. · 2.48 Impact Factor
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ABSTRACT: In order to elucidate the relationship between homocysteine and the fibrinolytic system, we examined the effect of homocysteine on plasminogen activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (tPA) gene expression and protein secretion in cultured human vascular endothelial and smooth muscle cells in vitro. PAI-1 mRNA and secreted protein levels were both enhanced by homocysteine in a dose dependent manner, with significant stimulation of PAI-1 secretion observed at concentrations greater than 0.5 mM homocysteine. In contrast, secretion and mRNA expression of tPA were not significantly altered by homocysteine stimulation. Secretion of TGFβ (transforming growth factor β) and TNFα (tumor necrosis factor α), possible regulators of PAI-1 expression and secretion, were not stimulated by treatment with 1.0 mM homocysteine. These results suggests that hyperhomocysteinemia-induced atherosclerosis and/or thrombosis may be caused by homocysteine-induced stimulation of PAI-1 gene expression and secretion in the vasuculatures by a mechanism independent from paracrine-autocrine activity of TGFβ and TNFα.
Biochemical and Biophysical Research Communications 06/2000; · 2.48 Impact Factor
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