Dietary salt and hypertension: new molecular targets add more spice

Khalil, Raouf A.

doi:10.1152/ajpregu.00600.2005

Cited by 26 publications

(22 citation statements)

References 59 publications

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“…Also, gene-targeting experiments in mice have identified over 30 genes, for which inactivating or activating mutations trigger chronic changes in BP. Most of these gene mutations involve an ion channel, an ion transporter, or a regulatory enzyme that could affect the renal function (84,110) (Fig. 2).…”

Section: Genetic Predisposing Factors In Renal Vascular Dysfunctionmentioning

confidence: 99%

Cellular mediators of renal vascular dysfunction in hypertension

Ponnuchamy¹,

Khalil²

2009

American Journal of Physiology-Regulatory, Integrative and Comp

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Ponnuchamy B, Khalil RA. Cellular mediators of renal vascular dysfunction in hypertension. Am J Physiol Regul Integr Comp Physiol 296: R1001-R1018, 2009. First published February 18, 2009 doi:10.1152/ajpregu.90960.2008.-The renal vasculature plays a major role in the regulation of renal blood flow and the ability of the kidney to control the plasma volume and blood pressure. Renal vascular dysfunction is associated with renal vasoconstriction, decreased renal blood flow, and consequent increase in plasma volume and has been demonstrated in several forms of hypertension (HTN), including genetic and salt-sensitive HTN. Several predisposing factors and cellular mediators have been implicated, but the relationship between their actions on the renal vasculature and the consequent effects on renal tubular function in the setting of HTN is not clearly defined. Gene mutations/ defects in an ion channel, a membrane ion transporter, and/or a regulatory enzyme in the nephron and renal vasculature may be a primary cause of renal vascular dysfunction. Environmental risk factors, such as high dietary salt intake, vascular inflammation, and oxidative stress further promote renal vascular dysfunction. Renal endothelial cell dysfunction is manifested as a decrease in the release of vasodilatory mediators, such as nitric oxide, prostacyclin, and hyperpolarizing factors, and/or an increase in vasoconstrictive mediators, such as endothelin, angiotensin II, and thromboxane A 2. Also, an increase in the amount/activity of intracellular Ca 2ϩ concentration, protein kinase C, Rho kinase, and mitogenactivated protein kinase in vascular smooth muscle promotes renal vasoconstriction. Matrix metalloproteinases and their inhibitors could also modify the composition of the extracellular matrix and lead to renal vascular remodeling. Synergistic interactions between the genetic and environmental risk factors on the cellular mediators of renal vascular dysfunction cause persistent renal vasoconstriction, increased renal vascular resistance, and decreased renal blood flow, and, consequently, lead to a disturbance in the renal control mechanisms of water and electrolyte balance, increased plasma volume, and HTN. Targeting the underlying genetic defects, environmental risk factors, and the aberrant renal vascular mediators involved should provide complementary strategies in the management of HTN. blood pressure; dietary salt; oxidative stress; cytokines; kidney; endothelium; vascular smooth muscle; extracellular matrix; matrix metalloproteinases THE ROLE OF THE KIDNEY IN the regulation of sodium and water balance and blood pressure (BP) is well recognized (53,55,128). A decrease in plasma volume and renal blood flow (RBF) stimulates renin release from the juxtaglomerular cells (JGCs) and activates the renin-angiotensin system (RAS). Renin transforms angiotensinogen to angiotensin I (ANG I), and angiotensin-converting enzyme (ACE) transforms ANG I to ANG II. ANG II stimulates the adrenal cortex to release aldosterone (Aldo), which acts on the rena...

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Section: Genetic Predisposing Factors In Renal Vascular Dysfunctionmentioning

confidence: 99%

Cellular mediators of renal vascular dysfunction in hypertension

Ponnuchamy¹,

Khalil²

2009

American Journal of Physiology-Regulatory, Integrative and Comp

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“…The volume overload triggers suppression of the renin-angiotensin-aldosterone system, leading to increased salt and water excretion and restoration of vascular volume toward normal (10 -12, 23). High dietary sodium may also promote vasoconstriction by changing plasma osmolarity, nuclear localization, and increased nuclear expression of vasoconstrictive stimuli, such as endothelin-1, release of ouabainlike factor, and activation of the sodium/calcium exchange mechanisms (1,2,18,20,28). Other studies have suggested that high dietary sodium may also affect vascular nitric oxide (NO) production (9).…”

mentioning

confidence: 99%

Effect of dietary sodium on vasoconstriction and eNOS-mediated vascular relaxation in caveolin-1-deficient mice

Pojoga

Yao²,

Sinha³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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RA. Effect of dietary sodium on vasoconstriction and eNOS-mediated vascular relaxation in caveolin-1-deficient mice. Am J Physiol Heart Circ Physiol 294: H1258-H1265, 2008. First published January 4, 2008 doi:10.1152/ajpheart.01014.2007.-Changes in dietary sodium intake are associated with changes in vascular volume and reactivity that may be mediated, in part, by alterations in endothelial nitric oxide synthase (eNOS) activity. Caveolin-1 (Cav-1), a transmembrane anchoring protein in the plasma membrane caveolae, binds eNOS and limits its translocation and activation. To test the hypothesis that endothelial Cav-1 participates in the dietary sodium-mediated effects on vascular function, we assessed vascular responses and nitric oxide (NO)-mediated mechanisms of vascular relaxation in Cav-1 knockout mice (Cav-1 Ϫ/Ϫ ) and wild-type control mice (WT; Cav-1 ϩ/ϩ ) placed on a high-salt (HS; 4% NaCl) or low-salt (LS; 0.08% NaCl) diet for 16 days. After the systolic blood pressure was measured, the thoracic aorta was isolated for measurement of vascular reactivity and NO production, and the heart was used for measurement of eNOS expression and/or activity. The blood pressure was elevated in HS mice treated with N G -nitro-L-arginine methyl ester and more so in Cav-1 Ϫ/Ϫ than WT mice and was significantly reduced during the LS diet. Phenylephrine caused vascular contraction that was significantly reduced in Cav-1 Ϫ/Ϫ (maximum 0.25 Ϯ 0.06 g/mg) compared with WT (0.75 Ϯ 0.22 g/mg) on the HS diet, and the differences were eliminated with the LS diet. Also, vascular contraction in response to membrane depolarization by high KCl (96 mM) was reduced in Cav-1 Ϫ/Ϫ (0.27 Ϯ 0.05 g/mg) compared with WT mice (0.53 Ϯ 0.12 g/mg) on the HS diet, suggesting that the reduced vascular contraction is not limited to a particular receptor. Acetylcholine (10 Ϫ5 M) caused aortic relaxation in WT mice on HS (23.6 Ϯ 3.5%) and LS (23.7 Ϯ 5.5%) that was enhanced in Cav-1 Ϫ/Ϫ HS (72.6 Ϯ 6.1%) and more so in Cav-1 Ϫ/Ϫ LS mice (93.6 Ϯ 3.5%). RT-PCR analysis indicated increased eNOS mRNA expression in the aorta and heart, and Western blots indicated increased total eNOS and phosphorylated eNOS in the heart of Cav-1 Ϫ/Ϫ compared with WT mice on the HS diet, and the genotypic differences were less apparent during the LS diet. Thus Cav-1 deficiency during the HS diet is associated with decreased vasoconstriction, increased vascular relaxation, and increased eNOS expression and activity, and these effects are altered during the LS diet. The data support the hypothesis that endothelial Cav-1, likely through an effect on eNOS activity, plays a prominent role in the regulation of vascular function during substantial changes in dietary sodium intake. endothelium; nitric oxide; vascular smooth muscle; blood pressure; hypertension HIGH-SALT (HS) DIET IS OFTEN associated with increased vascular volume (4, 15). The volume overload triggers suppression of the renin-angiotensin-aldosterone system, leading to increased salt and water excretion and restoration of v...

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“…1,2 Essential hypertension is heterogeneous and its expression is influenced by genetic and environmental factors. [2][3][4][5] The long-term regulation of blood pressure rests on renal and non-renal mechanisms, and abnormalities in the renal regulation of ion transport, intrinsic and extrinsic to the kidney, have been proposed to cause essential hypertension. [4][5][6] Several studies have reported that an impaired renal dopaminergic system may contribute to the pathogenesis of hypertension.…”

Section: Introductionmentioning

confidence: 99%

“…[2][3][4][5] The long-term regulation of blood pressure rests on renal and non-renal mechanisms, and abnormalities in the renal regulation of ion transport, intrinsic and extrinsic to the kidney, have been proposed to cause essential hypertension. [4][5][6] Several studies have reported that an impaired renal dopaminergic system may contribute to the pathogenesis of hypertension. 7,8 Dopamine receptors expressed in mammals belong to the a group of the rhodopsin family of G protein-coupled receptors.…”

Section: Introductionmentioning

confidence: 99%

“…The D 1 -like receptors, comprising D 1 and D 5 receptor subtypes, couple to the stimulatory G proteins G s and activate adenylyl cyclases. The D 2 -like receptors, comprising D 2 , D 3 and D 4 receptor subtypes, couple to the inhibitory G proteins G i and inhibit adenylyl cyclases and modulate ion channels. 7,8 There are increasing evidences for a direct interaction between D 1 -like and D 2 -like receptors in the kidney.…”

Section: Introductionmentioning

confidence: 99%

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