WHAT'S KNOWN ON THIS SUBJECT: High blood pressure in childhood predisposes people to hypertension in adulthood and is associated with early development of cardiovascular disease and risk for premature death. High sodium intake and overweight/ obesity are recognized as risk factors for hypertension in children. WHAT THIS STUDY ADDS:These results show that usual sodium intake was positively associated with systolic blood pressure and risk for pre-high blood pressure and high blood pressure among US children. The data indicate a synergistic interaction between sodium intake and weight status on risk for high blood pressure. abstract OBJECTIVE: To assess the association between usual dietary sodium intake and blood pressure among US children and adolescents, overall and by weight status. METHODS:Children and adolescents aged 8 to 18 years (n = 6235) who participated in NHANES 2003-2008 comprised the sample. Subjects' usual sodium intake was estimated by using multiple 24-hour dietary recalls. Linear or logistic regression was used to examine association between sodium intake and blood pressure or risk for pre-high blood pressure and high blood pressure (pre-HBP/HPB). RESULTS:Study subjects consumed an average of 3387 mg/day of sodium, and 37% were overweight/obese. Each 1000 mg per day sodium intake was associated with an increased SD score of 0.097 (95% confidence interval [CI] 0.006-0.188, ∼1.0 mm Hg) in systolic blood pressure (SBP) among all subjects and 0.141 (95% CI: -0.010 to 0.298, ∼1.5 mm Hg) increase among overweight/obese subjects. Mean adjusted SBP increased progressively with sodium intake quartile, from 106.2 mm Hg (95% CI: 105.1-107.3) to 108.8 mm Hg (95% CI: 107.5-110.1) overall (P = .010) and from 109.0 mm Hg (95% CI: 107.2-110.8) to 112.8 mm Hg (95% CI: 110.7-114.9; P = .037) among those overweight/obese. Adjusted odds ratios comparing risk for pre-HBP/HPB among subjects in the highest versus lowest sodium intake quartile were 2.0 (95% CI: 0.95-4.1, P = .062) overall and 3.5 (95% CI: 1.3-9.2, P = .013) among those overweight/obese. Sodium intake and weight status appeared to have synergistic effects on risk for pre-HBP/HPB (relative excess risk for interaction = 0.29 (95% CI: 0.01-0.90, P , .05).

Reactive oxygen species (ROS) are elevated in humans with hypertension many of which develop end-stage renal disease (ESRD), and antioxidant capacity is decreased. About one-half of essential hypertensives have a salt-sensitive type of hypertension, and the amount of renal damage that occurs in salt-sensitive hypertensives greatly exceeds that of non-salt-sensitive hypertensives. Antioxidant therapy can improve cardiovascular outcomes in humans but only if sufficient doses are used. Salt-sensitive hypertensive animal models, especially Dahl salt-sensitive rats, have been used to investigate the relationship between hypertension, ROS and end-stage renal damage. In experimental salt-sensitive hypertension, ROS increase and significant renal damage occur. In the Dahl salt-sensitive (S) rat on high Na for 3 weeks, renal damage is mild, renal levels of superoxide dismutase are decreased, and treatment with Tempol reduces arterial pressure. In the Dahl S rat on high Na for 5 weeks, renal damage is severe, GFR and renal plasma flow are decreased, and renal superoxide production is high. Treatment with vitamins C and E decreases renal superoxide production and renal damage and prevents the decrease in renal hemodynamics. Antioxidant treatment reduces arterial pressure, aortic superoxide production and renal inflammation in DOCA-salt rats, and decreases blood pressure and aortic superoxide release and increases bioactive nitric oxide in SHR stroke-prone rats. In conclusion, in both human and experimental salt-sensitive hypertension, superoxide production and renal damage are increased, antioxidant capacity is decreased, and antioxidant therapy can be helpful.

Abstract-The goal of this study was to test the hypothesis that oxidative stress in Dahl salt-sensitive (SS) rats on a high-sodium intake contributes to the progression of renal damage, the decreases in renal hemodynamics, and the development of hypertension. We specifically studied whether antioxidant therapy, using vitamins C and E, could help prevent renal damage and glomerular filtration rate (GFR) and renal plasma flow reductions and attenuate the increases in arterial pressure. Thirty-three 7-to 8-week old Dahl SS/Rapp strain rats were placed on either a high-sodium (8%) or a low-sodium (0.3%) diet with or without vitamin E (111 IU/d) in the food and 98 mg/d vitamin C in the drinking water for 5 weeks. Rats were equipped with indwelling arterial and venous catheters at day 21. By day 35 in the rats with high-sodium diet, vitamin C and E treatment significantly decreased renal cortical and medullary O 2 ⅐Ϫ release, mean arterial pressure, urinary protein excretion, glomerular necrosis, and renal tubulointerstitial damage. At this time, GFR significantly decreased in the high-sodium diet group (1.6Ϯ0.2 mL/min) when compared with either the high-sodium plus vitamins C and E (2.9Ϯ0.2 mL/min) or the low-sodium diet group (2.9Ϯ0.3 mL/min). In SS rats on high-sodium diet, renal plasma flow decreased 40%, and this reduced flow was restored by vitamin treatment. In Dahl salt-sensitive hypertension, increased oxidative stress plays an important role in the renal damage, decreases in renal hemodynamics, and increases in arterial pressure that occur. Antioxidant treatment with vitamins C and E improves renal dysfunction, lessens renal injury, and decreases arterial pressure in Dahl salt-sensitive hypertension. Key Words: antioxidants Ⅲ hemodynamics Ⅲ hypertension Ⅲ renal disease H ypertension continues to be a major cardiovascular risk factor and a major contributor to end-stage renal disease (ESRD). In particular, patients with salt-sensitive hypertension are much more likely to experience ESRD compared with salt-insensitive hypertensive patients. 1 Recent studies in humans and in animal models of salt-sensitive hypertension indicate that an increase in oxidative stress is associated with a progressive elevation in arterial pressure and a reduction in renal function. However, the mechanisms underlying the progression of hypertension and ESRD in salt-sensitive hypertension are not clear.A model that closely mimics human salt-sensitive essential hypertension is the Dahl S rat. Common traits shared by salt-sensitive humans and the S rat include progressive increases in arterial pressure and renal damage, 2,3 increased O 2 ⅐Ϫ release, 4 and endothelial dysfunction. 5 Recently, we have shown that the oxidative stress that occurs in Dahl S rats on high-sodium intake for 3 weeks contributes to the increase in arterial pressure, but renal hemodynamics were unchanged in high-sodium diet rats and renal damage was minor. 6 In contrast, renal damage is much more severe in S rats on high-sodium diet for 5 weeks, with progressive ...

Oxidative stress occurs in a tissue or in the whole body when the total oxidant production exceeds the antioxidant capacity. Recent studies in human essential hypertension indicate that free radical production is increased and antioxidant levels are decreased, and more than one-half of these hypertensives have a salt-sensitive type of hypertension with progressive renal damage. Increased oxidative stress may also play a critical role in animal models of salt-sensitive hypertension. The stroke-prone spontaneously hypertensive rats (SHRSP) exhibits salt-sensitivity, vascular release of superoxide is increased, and total plasma antioxidant capacity is decreased. The superoxide release in the SHRSP rats inactivates nitric oxide, and superoxide dismutase (SOD) administration returns the bioactive nitric oxide levels to normal. The deoxycorticosterone acetate (DOCA)-salt hypertensive rat is salt-sensitive, aortic superoxide production is increased, and renal inflammation is significant. Treatment of the DOCA-salt rats with apocynin, an NADPH oxidase inhibitor, decreased aortic superoxide production and decreased arterial pressure. The Dahl salt-sensitive (S) rat has increased mesenteric microvascular and renal superoxide production and increased plasma levels of H2O2. The renal protein expression of SOD is decreased in the kidney of Dahl S rats, and long-term administration of Tempol, a superoxide mimetic, significantly decreased arterial pressure and renal damage. In conclusion, both human hypertension and experimental models of salt-sensitive hypertension have increased superoxide release, decreased antioxidant capacity and elevated renal damage.

Tian N, Gu JW, Jordan S, Rose RA, Hughson MD, Manning RD Jr. Immune suppression prevents renal damage and dysfunction and reduces arterial pressure in salt-sensitive hypertension. Am J Physiol Heart Circ Physiol 292: H1018 -H1025, 2007. First published October 13, 2006; doi:10.1152/ajpheart.00487.2006.-The goal of this study was to test the hypothesis that renal infiltration of immune cells in Dahl S rats on increased dietary sodium intake contributes to the progression of renal damage, decreases in renal hemodynamics, and development of hypertension. We specifically studied whether anti-immune therapy, using mycophenolate mofetil (MMF), could help prevent increases in renal NF-B activation, renal infiltration of monocytes/macrophages, renal damage, decreases in glomerular filtration rate (GFR) and renal plasma flow, and increases in arterial pressure. Seventy-four 7-to 8-wk-old Dahl S, Rapp strain rats were maintained on an 8% Na, 8% Na ϩ MMF (20 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ), 0.3% Na, or 0.3% Na ϩ MMF diet for 5 wk. Arterial and venous catheters were implanted at day 21. By day 35, renal NF-B in 8% Na rats was 47% higher than in 0.3% Na rats and renal NF-B was 41% lower in 8% Na ϩ MMF rats compared with the 8% Na group. MMF treatment significantly decreased renal monocyte/macrophage infiltration and renal damage and increased GFR and renal plasma flow. In high-NA Dahl S rats mean arterial pressure increased to 182 Ϯ 5 mmHg, and MMF reduced this arterial pressure to 124 Ϯ 3 mmHg. In summary, in Dahl S rats on high sodium intake, treatment with MMF decreases renal NF-B and renal monocyte/macrophage infiltration and improves renal function, lessens renal injury, and decreases arterial pressure. This suggests that renal infiltration of immune cells is associated with increased arterial pressure and renal damage and decreasing GFR and renal plasma flow in Dahl salt-sensitive hypertension. renal failure; macrophages; renal hemodynamics; nuclear factor-B SEVERAL MECHANISMS have been found to contribute to the etiology of salt-sensitive hypertension, including reduced levels of NO (7) and elevated oxidative stress (12,29). In addition to these factors, there is emerging evidence indicating that the immune system may play an important role in salt-sensitive hypertension.In several models of hypertension, renal tubulointerstitial infiltration of macrophages and lymphocytes occurs. Renal immunocompetent cells have been found in DOCA hypertension (27), post-angiotensin II (ANG) salt-sensitive hypertension (21), hypertension following NO inhibition (20), protein overload nephropathy (1), the spontaneously hypertensive rate (SHR) (22) and the double-transgenic rat (dTGR) that has human renin and angiotensinogen genes (18). Anti-immune therapy administered to each of the above models of hypertension successfully decreased arterial pressure (24).Dahl salt-sensitive hypertension is characterized by increases in oxidative stress, severe renal damage, and decreases in renal hemodynamics (29); however, the role of renal immune cell infil...

Tian N, Moore RS, Braddy S, Rose RA, Gu JW, Hughson MD, Manning RD Jr. Interactions between oxidative stress and inflammation in salt-sensitive hypertension. Am J Physiol Heart Circ Physiol 293: H3388-H3395, 2007. First published October 5, 2007; doi:10.1152/ajpheart.00981.2007.-The goal of this study was to test the hypothesis that increases in oxidative stress in Dahl S rats on a high-salt diet help to stimulate renal nuclear factor-B (NF-B), renal proinflammatory cytokines, and chemokines, thus contributing to hypertension, renal damage, and dysfunction. We specifically studied whether antioxidant treatment of Dahl S rats on high Na intake would decrease renal inflammation and thus attenuate the hypertensive and adverse renal responses. Sixty-four 7-to 8-wk-old Dahl S or R/Rapp strain rats were maintained for 5 wk on high Na (8%) or high Na ϩ vitamins C (1 g/l in drinking water) and E (5,000 IU/kg in food). Arterial and venous catheters were implanted at day 21. By day 35 in the high-Na S rats, antioxidant treatment significantly increased the renal reduced-to-oxidized glutathione ratio and decreased renal cortical H 2O2 and O2•Ϫ release and renal NF-B. Antioxidant treatment with vitamins C and E in high-Na S rats also decreased renal monocytes/macrophages in the glomeruli, cortex, and medulla, decreased tumor necrosis factor-␣ by 39%, and decreased monocyte chemoattractant protein-1 by 38%. Vitamin-treated, high-Na S rats also experienced decreases in arterial pressure, urinary protein excretion, renal tubulointerstitial damage, and glomerular necrosis and increases in glomerular filtration rate and renal plasma flow. In conclusion, antioxidant treatment of high-Na Dahl S rats decreased renal inflammatory cytokines and chemokines, renal immune cells, NF-B, and arterial pressure and improved renal function and damage. renal failure; cytokines; chemokines; renal hemodynamics; salt-sensitivity; nuclear factor-B STUDIES IN HUMAN AND EXPERIMENTAL HYPERTENSION have shown that increases in oxidative stress may play an important role in the etiology and maintenance of increased blood pressure. Increased oxidative stress has been found in the spontaneously hypertensive rat (SHR), the stroke-prone SHR, DOCA-salt hypertensive rats, and the Dahl salt-sensitive (S) rat (5,6,10,21,22,41,49). In addition, evidence for increased renal oxidative stress has been found in lead-induced hypertension (48), coarctation of the aorta (3), and in the Dahl S rat (22, 43).There is considerable evidence for the involvement of the immune system in hypertension. Studies in several models of experimental hypertension have found renal invasion of lymphocytes and macrophages (24,29,31,40,45). Anti-immune therapy administered to these models of hypertension successfully decreased arterial pressure (32) and renal levels of immunocompetent cells.Our laboratory has shown that the Dahl S rat, when challenged with a high-salt diet, experiences both oxidative stress and inflammation (45), and this is associated with hypertension and considerable r...

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The goal of this study was to test the hypothesis that NADPH oxidase contributes importantly to renal cortical oxidative stress and inflammation, as well as renal damage and dysfunction, and increases in arterial pressure. Fifty-four 7- to 8-wk-old Dahl salt-sensitive (S) or R/Rapp strain rats were maintained for 5 wk on a high sodium (8%) or high sodium + apocynin (1.5 mmol/l in drinking water). Arterial and venous catheters were implanted on day 21. By day 35 in the high-Na S rats, mRNA expression of renal cortical gp91phox, p22phox, p47phox, and p67phox NADPH subunits in S rats increased markedly, and treatment of high-Na S rats with the NADPH oxidase inhibitor apocynin resulted in significant decreases in mRNA expression of these NADPH oxidase subunits. At the same time, in apocynin-treated S rats 1) renal cortical GSH/GSSG ratio increased, 2) renal cortical O2(.-) release and NADPH oxidase activity decreased, and 3) renal glomerular and interstitial damage markedly fell. Apocynin also decreased renal cortical monocyte/macrophage infiltration, and apocynin, but not the xanthine oxidase inhibitor allopurinol, attenuated decreases in renal hemodynamics and lowered arterial pressure. These data suggest that NADPH oxidase plays an important role in causing renal cortical oxidative stress and inflammation, which lead to decreases in renal hemodynamics, renal cortical damage, and increases in arterial pressure.