Association of Genetic Variants of Klotho with BP Responses to Dietary Sodium or Potassium Intervention and Long-Term BP Progression.

OBJECTIVES: Klotho (KL) plays pivotal roles in the progression of salt-sensitive hypertension. Salt-sensitive hypertension was associated with KL genotypes. We aimed to explore the association of common genetic variants of KL with individual blood pressure (BP) responses to sodium and potassium through a dietary intervention study as well as long-term BP progression. METHODS: We conducted family-based dietary interventions among 344 participants from 126 families in rural villages of northern China in 2004. Subjects sequentially underwent a baseline diet, a low-salt diet (51.3 mmol/day Na), a high-salt diet (307.8 mmol/day Na), and a high-salt + potassium supplementation diet (307.8 mmol/day Na + 60 mmol/day K). After dietary intervention, we followed up with these participants in 2009 and 2012. The associations between 6 single-nucleotide polymorphisms (SNPs) of KL and phenotypes were analyzed through a linear mixed-effects model. RESULTS: SNPs rs211247 and rs1207568 were positively correlated with the BP response to high-salt diet in the dominant model after adjusting for confounders (ß = 1.670 and 2.163, p = 0.032 and 0.005, respectively). BPs rs526906 and rs525014 were in a haplotype block. Block rs526906-rs525014 was positively correlated with diastolic BP response to potassium and potassium sensitivity in the additive model (ß = 0.845, p = 0.032). In addition, regression analysis indicated that rs211247 was associated with long-term systolic BP alterations after 8 years of follow-up in the recessive model (ß = 20.47, p = 0.032). CONCLUSIONS: Common variants of the KL gene might modify individual BP sensitivity to sodium or potassium and influence the long-term progression of BP, suggesting a potential role in the development of salt-sensitive hypertension. Thus, KL may be a new early intervention target for salt-sensitive hypertension.

The responses of the inflammatory marker, pentraxin 3, to dietary sodium and potassium interventions.

Pentraxin-3 is a sensitive marker of inflammation that plays dual roles, pathogenic and cardioprotective, in the progression of cardiovascular diseases. Inflammation is intimately involved in salt-induced hypertension. We investigated the responses of pentraxin-3 to sodium and potassium supplementation to elucidate the potential role of pentraxin-3 in salt-induced hypertension. A total of 48 participants from northwest China were enrolled. All participants were maintained on a 3-day normal diet, which was sequentially followed by a 7-day low-sodium diet, a 7-day high-sodium diet, and a 7-day high-sodium plus potassium diet. Plasma concentrations of pentraxin-3 were assessed using ELISA. Plasma pentraxin-3 decreased significantly during the low-salt period compared to baseline (0.57 ± 0.19 ng/mL vs 0.72 ± 0.33 ng/mL, P = .012) and increased during the high-salt period (0.68 ± 0.26 ng/mL vs 0.57 ± 0.19 ng/mL, P = .037). Potassium supplementation inhibited salt-induced increase in pentraxin-3 (0.56 ± 0.21 ng/mL vs 0.68 ± 0.26 ng/mL, P = .015). Ln-transformed pentraxin-3 at baseline was inversely correlated with BMI (r = -.349, P = .02), DBP (r = -.414, P = .005), MAP (r = -.360, P = .017). We found a positive correlation between the ln-transformed concentrations of pentraxin-3 and 24-hour urinary sodium during low and high Na+ periods (r = .269, P = .012) and a negative relationship with 24 hours urinary potassium excretion during high-salt and high-salt plus potassium periods (r = -.246, P = .02). These correlations remained significant after adjusting for confounders. Pentraxin-3 responses were more prominent in salt-sensitive individuals than salt-resistant individuals. Dietary salt and potassium interventions significantly altered circulating pentraxin-3.

Short-Term High-Salt Diet Increases Corin Level to Regulate the Salt-Water Balance in Humans and Rodents.

BACKGROUND: Dietary sodium and potassium affect the fluctuation in blood pressure (BP) and renal function. Corin, with its enzymatic activity to convert pro-atrial natriuretic peptide (pro-ANP) to biologically active ANP, regulates BP, cardiac, and renal functions. We investigated whether corin expression responds to a high-salt (HS) diet to regulate salt and water balance. METHODS: Forty-two volunteers followed 3 sequential diets for 7 days each: a low-salt (LS) diet (3.0 g/day NaCl), a HS diet (18.0 g/day NaCl), followed by an HS diet with K+ supplementation (HS + K+) (18.0 g/day NaCl and 4.5 g/day KCl). RESULTS: Corin level was higher with the HS diet than the LS and HS + K+ diets and was positively correlated with systolic BP (SBP) and 24-hour urinary Na+ and microalbumin (U-mALB) excretion. In rodents, serum and renal levels of corin were transiently increased with the HS diet and were decreased if the HS diet was continued for up to 7 days. HS loading increased SBP, 24-hour urinary Na+, U-mALB excretion, and the expression of proprotein convertase subtilisin/kexin-6 (PCSK6), a corin activator. Knockdown of PCSK6 or corin in high salt-treated M1-cortical collecting duct (M1-CCD) cells increased the expression of aquaporin 2 (AQP2) and ß-epithelial Na+ channel (ß-ENaC). CONCLUSIONS: Short-term HS may induce the PCSK6-corin-ANP-AQP2/ß-ENaC pathway in the kidney. Enhanced serum corin level in humans and rodents is positively correlated with HS-induced SBP and 24-hour urinary Na+ and U-mALB excretion, which suggests that corin is involved in the salt-water balance in response to HS intake. CLINICAL TRIALS REGISTRATION: Public Trials Registry Number NCT02915315.

Effects of salt loading and potassium supplement on the circadian blood pressure profile in salt-sensitive Chinese patients.

BACKGROUND AND OBJECTIVE: Salt-sensitive (SS) patients more frequently showed a nondipper blood pressure pattern and were associated with more serious target organ damage than non-SS patients. We aimed to investigate whether potassium supplement can improve the blunted nocturnal blood pressure fall in SS patients exposed to a high-salt diet. PATIENTS AND METHODS: Approximately 49 normotensive and mildly hypertensive Chinese patients received a study protocol of a 3 days of baseline examination, 7 days of a low-salt diet (3 g NaCl/day), 7 days of a high-salt diet (18 g NaCl/day), and 7 days of a high-salt diet with a potassium supplement (18 g NaCl and 4.5 g KCl/day). The 24 h ambulatory blood pressure was determined at the end of each period. RESULTS: A total of 14 patients were classified as SS according to the at least 10% increase in their 24-h mean arterial pressure after high-salt loading. The night-to-day blood pressure ratio was significantly higher in SS patients than in non-SS patients during the high-salt loading period (systolic 0.96±0.01 vs. 0.89±0.01, P<0.01; diastolic 0.96±0.01 vs. 0.92±0.01, P<0.05). Compared with the high-salt loading period, the night-to-day blood pressure ratio was significantly reversed by potassium supplement in SS patients (systolic 0.91±0.01 vs. 0.96±0.01, P<0.05; diastolic 0.91±0.01 vs. 0.96±0.01, P<0.05). CONCLUSION: Potassium supplement can improve the blunted nocturnal blood pressure fall in SS patients exposed to a high-salt diet, but the related mechanism needs to be studied further.

Effects of Salt Loading on Plasma Osteoprotegerin Levels and Protective Role of Potassium Supplement in Normotensive Subjects.

BACKGROUND: Excess dietary salt is strongly correlated with cardiovascular disease, morbidity, and mortality. Conversely, potassium likely elicits favorable effects on cardiovascular disorders. In epidemiological studies, increased plasma osteoprotegerin (OPG) concentrations are associated with atherosclerosis and vascular deaths. Our study was designed to examine the effects of salt intake and potassium supplementation on plasma OPG levels in normotensive subjects.Methods and Results:The 18 normotensive subjects were selected from a rural community in China. They were sequentially maintained on low-salt diet for 7 days (3 g/day, NaCl), high-salt diet for 7 days (18 g/day), and high-salt diet with potassium supplementation for 7 days (18 g/day of NaCl+4.5 g/day of KCl). High-salt intake enhanced plasma OPG levels (252.7±13.9 vs. 293.4±16.1 pg/mL). This phenomenon was abolished through potassium supplementation (293.4±16.1 vs. 235.1±11.3 pg/mL). Further analyses revealed that the OPG concentration positively correlated with 24-h urinary sodium excretion (r=0.497, P<0.01). By contrast, OPG concentration negatively correlated with 24-h urinary potassium excretion (r=0.594, P<0.01). CONCLUSIONS: Salt loading can enhance the production of circulating OPG. Potassium supplementation can reverse the effects of excessive OPG. Our study results may improve our understanding of the roles of salt and potassium in the risk of cardiovascular disorders.

Oral CoQ10 attenuates high salt-induced hypertension by restoring neurotransmitters and cytokines in the hypothalamic paraventricular nucleus.

High salt intake leads to an increase in some proinflammatory cytokines and neurotransmitters involved in the pathogenesis of hypertension. The purpose of this work was to know if oral administration of anti-oxidant and free-radical scavenger CoQ10 may attenuate high salt-induced hypertension via regulating neurotransmitters and cytokines in the hypothalamic paraventricular nucleus (PVN). Adult male Sprague-Dawley (SD) rats were fed with a normal salt diet (NS, 0.3% NaCl) or a high salt diet (HS, 8% NaCl) for 15 weeks to induce hypertension. These rats received CoQ10 (10 mg/kg/day) dissolved in olive oil was given by gavage (10 mg/kg/day) for 15 weeks. HS resulted in higher mean arterial pressure (MAP) and the sympathetic nerve activity (RSNA). These HS rats had higher PVN levels of norepinephrine (NE), tyrosine hydroxylase (TH), interleukin (IL)-1ß, NOX2 and NOX4, lower PVN levels of gamma-aminobutyric acid (GABA), IL-10, copper/zinc superoxide dismutase (Cu/Zn-SOD) and the 67-kDa isoform of glutamate decarboxylase (GAD67), as compared with NS group. CoQ10 supplementation reduced NE, TH, IL-1ß, NOX2 and NOX4 in the PVN, and induced IL-10, Cu/Zn-SOD and GAD67 in the PVN. These findings suggest that CoQ10 supplementation restores neurotransmitters and cytokines in the PVN, thereby attenuating high salt-induced hypertension.

Effects of salt intake and potassium supplementation on renalase expression in the kidneys of Dahl salt-sensitive rats.

Renalase is currently the only known amine oxidase in the blood that can metabolize catecholamines and regulate sympathetic activity. High salt intake is associated with high blood pressure (BP), possibly through the modulation of renalase expression and secretion, whereas potassium can reverse the high salt-mediated increase in blood pressure. However, whether potassium could also modulate BP through renalase is unclear. In this study, we aim to investigate how salt intake and potassium supplementation affect the level of renalase in rats. Eighteen salt-sensitive (SS) and 18 SS-13BN rats were divided into six groups, receiving normal salt (0.3% NaCl), high salt (8% NaCl) and high salt/potassium (8% NaCl and 8% KCl) dietary intervention for four weeks. At the end of experiments, blood and kidneys were collected for analysis. mRNA level of renalase was measured by quantitative real-time PCR and protein level was determined by Western blot. We found that mRNA and protein levels of renalase in the kidneys of SS and SS-13BN rats were significantly decreased (P < 0.05) after high salt intervention, whereas dopamine in plasma was increased (P < 0.05) compared with rats received normal salt, suggesting that salt may induce salt-sensitive hypertension through inhibition of renalase expression. We also found increased mRNA level and protein level of renalase, decreased catecholamine levels in plasma, and decreased BP in SS rats treated with high salt/potassium, compared with that of the high salt SS group. Taken together, the salt-induced increase and potassium-induced decrease in BP could be mediated through renalase. More studies are needed to confirm our findings and understand the underlying mechanisms.

Common Variants in Serum/Glucocorticoid Regulated Kinase 1 (SGK1) and Blood Pressure Responses to Dietary Sodium or Potassium Interventions: A family-Based Association Study.

BACKGROUND/AIMS: Serum/Glucocorticoid Regulated Kinase 1 (SGK1) plays a significant role in regulating renal Na(+) reabsorption, K(+) secretion, and blood pressure (BP). This study aimed to assess the association of common genetic variants in the SGK1 gene with BP responses to controlled dietary sodium or potassium interventions. METHODS: A total of 334 subjects from 124 families were recruited from the rural areas of northern China. After a three-day baseline observation, they were sequentially maintained a seven-day low-sodium diet (3g/day of NaCl or 51.3 mmol/day of sodium), a seven-day high-sodium diet (18 g/day of NaCl or 307.8 mmol/day of sodium) and a seven-day high-sodium plus potassium supplementation intervention (4.5 g/day of KCl or 60 mmol/day of potassium). Six single-nucleotide polymorphisms (SNPs) in the SGK1 gene were selected. RESULTS: After adjustment for multiple testing, SNP rs9376026 was significantly associated with diastolic BP (DBP) and mean arterial pressure (MAP) responses to low-sodium intervention (P = 0.018 and 0.022, respectively). However, the associations between selected SNPs in the SGK1 gene and BP responses to high-sodium or high-sodium plus potassium-supplementation intervention did not reach statistical significance. In addition, SNP rs9389154 and two other SNPs (rs1763509 and rs9376026) were associated respectively with systolic BP (SBP) and DBP at baseline (P = 0.040, 0.032, and 0.031, respectively). SNP rs3813344 was significantly associated with SBP, DBP, and MAP (P = 0.049, 0.015 and 0.018, respectively). CONCLUSION: Our study indicates that the genetic polymorphism in the SGK1 gene is significantly associated with BP responses to dietary sodium intervention.

Effect of salt intake and potassium supplementation on urinary renalase and serum dopamine levels in Chinese adults.

OBJECTIVE: The aim of our study was to assess the effects of altered salt and potassium intake on urinary renalase and serum dopamine levels in humans. METHODS: Forty-two subjects (28­65 years of age) were selected from a rural community of northern China. All subjects were sequentially maintained on a low-salt diet for 7 days (3.0 g/day of NaCl), a high-salt diet for an additional 7 days (18.0 g/day of NaCl), and a high-salt diet with potassium supplementation for a final 7 days (18.0 g/day of NaCl + 4.5 g/day of KCl). RESULTS: Urinary renalase excretions were significantly higher during the high-salt diet intervention than during the low-salt diet. During high-potassium intake, urinary renalase excretions were not significantly different from the high-salt diet, whereas they were significantly higher than the low-salt levels. Serum dopamine levels exhibited similar trends across the interventions. Additionally, a significant positive relationship was observed between the urine renalase and serum dopamine among the different dietary interventions. Also, 24-hour urinary sodium excretion positively correlated with urine renalase and serum dopamine in the whole population. CONCLUSIONS: The present study indicates that dietary salt intake and potassium supplementation increase urinary renalase and serum dopamine levels in Chinese subjects.

Genetic variants in renalase and blood pressure responses to dietary salt and potassium interventions: a family-based association study.

BACKGROUND/AIMS: Renalase (gene name RNLS), a recently discovered enzyme with monoamine oxidase activity, is implicated in the degradation of catecholamines. Recent studies indicate that common variations in the gene with RNLS are associated with hypertension. The aim of this study was to examine the association between genetic variants in RNLS and blood pressure (BP) responses to strict dietary interventions of salt and potassium intake. METHODS: A total of 334 subjects from 124 families were selected and sequentially maintained on a low-salt diet for 7 days (3.0 g/day, NaCl), then a high-salt diet for 7 days (18.0 g/day, NaCl), high-salt diet with potassium supplementation for another 7 days (4.5 g/day, KCl). RESULTS: SNPs rs919115 and rs792205 of the RNLS gene were significantly associated with diastolic BP (DBP) and mean arterial pressure (MAP) responses to high-salt intervention. In addition, rs12356177 was significantly associated with systolic BP (SBP) and DBP responses to low-salt diet, and SBP, DBP or MAP during the high-salt intervention. Unfortunately, no associations for the 7 RNLS SNPs with BP response to high-salt diet with potassium supplementation reached nominal statistical significance. CONCLUSIONS: This family-based study indicates that genetic variants in the RNLS gene are significantly associated with BP responses to dietary salt intake.

Effect of salt intake and potassium supplementation on serum renalase levels in Chinese adults: a randomized trial.

Renalase, a recently discovered enzyme released by the kidneys, breaks down blood-borne catecholamines and may thus regulate blood pressure (BP). Animal studies have suggested that high levels of dietary salt might reduce blood and kidney renalase levels. We conducted a randomized trial to assess the effects of altered salt and potassium intake on serum renalase levels and the relationship between serum renalase levels and BP in humans.Forty-two subjects (28-65 years of age) were selected from a rural community of northern China. All subjects were sequentially maintained on a low-salt diet for 7 days (3.0 g/day of NaCl), a high-salt diet for additional 7 days (18.0 g/day of NaCl), and a high-salt diet with potassium supplementation for final 7 days (18.0 g/day of NaCl + 4.5 g/day of KCl).Serum renalase levels were significantly higher than baseline levels during the low-salt diet intervention period. Renalase levels decreased with the change from the low-salt to high-salt diet, whereas dietary potassium prevented the decrease in serum renalase induced by the high-salt diet. There was a significant inverse correlation between the serum renalase level and 24-h urinary sodium excretion. No significant correlation was found between the renalase level and BP among the different dietary interventions.The present study indicates that variations in dietary salt intake and potassium supplementation affect the serum renalase concentration in Chinese subjects.

Salt loading on plasma asymmetrical dimethylarginine and the protective role of potassium supplement in normotensive salt-sensitive asians.

Asymmetrical dimethylarginine (ADMA) is an endogenous inhibitor of NO synthase. Because endothelial NO pathway is compromised in patients with salt-sensitive hypertension, we investigated whether the plasma ADMA can be modulated by chronic salt loading in normotensive salt-sensitive persons and its relationship with NO, and we further determined whether or not dietary potassium supplementation can reverse them. Sixty normotensive subjects (aged 20 to 60 years) were selected from a rural community of Northern China. All of the people were sequentially maintained on a low-salt diet for 7 days (3 g/day, NaCl), then a high-salt diet for 7 days (18 g/day), and high-salt diet with potassium supplementation for another 7 days (4.5 g/day, KCl). After salt loading, the plasma ADMA concentrations increased significantly in salt-sensitive subjects (0.89+/-0.02 micromol/L versus 0.51+/-0.02 micromol/L; P<0.05), whereas the plasma NOx levels reduced considerably (41.8+/-2.1 micromol/L versus 63.5+/-2.1 micromol/L; P<0.01). All of the abnormalities normalized when dietary potassium were supplemented (0.52+/-0.03 micromol/L versus 0.89+/-0.02 micromol/L for ADMA and 58.1+/-0.9 micromol/L versus 41.8+/-2.1 micromol/L for NOx). Statistically significant correlations were found among plasma ADMA level, the mean blood pressure, and the level of NO after salt loading in normotensive salt sensitive individuals. Our study indicates that high dietary potassium intake reduces blood pressure and ADMA levels while increasing NO bioactivity in normotensive salt-sensitive but not salt-resistant Asian subjects after salt loading.

[Endothelial function evaluation in salt-sensitive normotensive and mild hypertensive subjects and effects of potassium supplement].

OBJECTIVE: Salt-sensitivity plays an important role in essential hypertension and is associated with more severe target organ injury and higher mortality in patients with essential hypertension. However, the pathologic mechanism of salt-sensitivity is poorly understood and endothelial dysfunction might be involved in salt-sensitive hypertension. We, therefore, observed the endothelial function changes by measuring plasma and urine nitric oxide (NO) concentrations in salt-sensitive (SS) normotensive and mild hypertensive subjects underwent various salt loading protocols and the effects of potassium supplement. METHODS: Thirty-nine normotensive and mild hypertensive subjects (< 160/100 mm Hg), aged 16-60, were enrolled and the study protocol is as follows: 3 days baseline investigation, 1 week low-salt loading (3 g/day), 1 week. high-salt loading (18 g/day) and 1 week high-salt loading plus potassium chloride (4.5 g/day). RESULTS: Plasma and urine NO levels were significantly lower in SS (n = 8) subjects at baseline, low-salt and high-salt loading phases compared with salt-resistant subjects (SR, n = 31) and oral potassium supplement to SS subjects with high salt loading significantly increased plasma and urine NO levels. CONCLUSION: Endothelial function is impaired in normotensive and mild hypertensive SS subjects. Oral potassium supplement could improve endothelial function in normotensive and mild hypertensive SS subjects.

[Long term observation in effects of potassium and calcium supplementation on arterial blood pressure and sodium metabolism in adolescents with higher blood pressure].

OBJECTIVE: To investigate the effects of potassium and calcium supplementation in table salt on reduction of arterial blood pressure and sodium metabolism in adolescents with higher blood pressure. METHODS: A single blind placebo-controlled trial was carried out for two years in 220 adolescents with higher blood pressure, aged 18 - 22 years, who were randomly divided into supplementary group (n = 110) and control group (n = 110). Each of the subjects in the supplementary group and their family members was given 10 mmol of potassium and 10 mmol of calcium mixed in their table salt daily for 24 months. RESULTS: Night urinary sodium and potassium excretion increased (urinary Na(+), P < 0.05; urinary K(+), P < 0.01) and blood pressure lowered by 5.3 mm Hg/1.8 mm Hg in average from the baseline in the supplementary group two years after potassium and calcium supplementation, as compared with that in the control group increased by (1.3/1.7) mm Hg. CONCLUSIONS: Adequate supplement of potassium and calcium in daily table salt intake was an effective way to prevent form hypertension and could promote their urinary sodium excretion and reduction of arterial blood pressure in adolescents with higher blood pressure.