Associations of E-proteinoid 3 receptor genetic polymorphisms with salt sensitivity, longitudinal blood pressure changes, and hypertension incidence in Chinese adults.

The E-proteinoid 3 receptor (PTGER3), a member of the prostaglandin E2 (PGE2) subtype receptor, belongs to the G-protein-coupled superfamily of receptors. Animal studies have demonstrated its involvement in salt sensitivity by regulating sodium reabsorption. This study aimed to investigate the association between genetic variants of PTGER3 and salt sensitivity, longitudinal blood pressure (BP) changes, and the incidence of hypertension in Chinese adults. A chronic salt intake intervention was conducted involving 514 adults from 124 families in the 2004 Baoji Salt-Sensitivity Study Cohort in northern China. These participants followed a 3-day regular baseline diet, followed by a 7-day low-salt diet (3.0 g/d) and a 7-day high-salt diet (18 g/d), and were subsequently followed for 14 years. The findings revealed a significant relationship between the single nucleotide polymorphism (SNP) rs17482751 of PTGER3 and diastolic blood pressure (DBP) response to high salt intervention. Additionally, SNPs rs11209733, rs3765894, and rs2268062 were significantly associated with longitudinal changes in systolic blood pressure (SBP), DBP, and mean arterial pressure (MAP) during the 14-year follow-up period. SNP rs6424414 was significantly associated with longitudinal changes in DBP over 14 years. Finally, SNP rs17482751 showed a significant correlation with the incidence of hypertension over 14 years. These results emphasize the significant role of PTGER3 gene polymorphism in salt sensitivity, longitudinal BP changes, and the development of hypertension in the Chinese population.

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.

Associations of risk factors in childhood with arterial stiffness 26 years later: the Hanzhong adolescent hypertension cohort.

OBJECTIVE: The relationship between childhood risk factors and long-term arterial stiffness was explored. METHODS: A baseline survey was conducted in 4623 school children aged 6-15 years in rural areas of Hanzhong city, Shaanxi, in 1987. According to three independent measurements of SBP in 1987, 1989, and 1992, cases of the same age and sex with continuous SBP at least 75 percentile were classified as the high-blood pressure (BP) group, whereas those with SBP less than 50 percentile were classified as the normal-BP group. The cohort was followed up again after 26 years (in 2013). Blood biochemistry indexes, including fasting glucose, uric acid, and blood lipid, were measured. Brachial-ankle pulse wave velocity (baPWV) was recorded by noninvasive automatic waveform analyzer. RESULTS: Follow-up rate was 71.6%. The high-BP group had a higher incidence of hypertension (39.5 vs. 18.0%, P < 0.01) and baPWV (1337.2 ±â€Š198.3 vs. 1271.7 ±â€Š204.3 cm/s, P = 0.028) than the normal-BP group during the follow-up period. Positive correlation was found during follow-up between baPWV and childhood SBP, as well as SBP, DBP, BMI, heart rate, total cholesterol, low-density lipoprotein cholesterol, triacylglycerol, fasting glucose, and uric acid in adulthood (all P < 0.05). Results from stepwise multivariate regression analysis showed that men, family history of hypertension, SBP at both baseline and follow-up, fasting glucose, and uric acid in adulthood are independent impact factors of baPWV in adults. CONCLUSION: Higher SBP in children and adolescents, family history of hypertension, and male sex may increase the risk of developing long-term arterial stiffness.

Association of Renalase SNPs rs2296545 and rs2576178 with the Risk of Hypertension: A Meta-Analysis.

BACKGROUND/AIMS: Two renalase single nucleotide polymorphisms (SNPs) rs2296545 and rs2576178 have been reported to be associated with the susceptibility to hypertension (HT). Given the inconsistent results, we conducted a meta-analysis to assess the association between these two SNPs and the risk of HT. METHODS: Electronic databases were systematically searched to find relevant studies. Subgroup analysis was conducted according to the different concomitant diseases and ethnicities in the study population. Pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated using fixed-effect or random-effect models. RESULTS: A total of six case-control studies on rs2296545 and six studies on rs2576178 were included. In the combined analysis, results showed a significant association between SNP rs2296545 and risk of HT in all genetic models (dominant model CG+CC/GG: OR = 1.43, 95% CI = 1.24-1.65; recessive model CC/CG+GG: OR = 1.36, 95% CI = 1.09-1.69; codominant model CC/GG: OR = 1.63, 95% CI = 1.20-2.20, CG/GG: OR = 1.30, 95% CI = 1.12-1.52; allelic model C/G: OR = 1.29, 95% CI = 1.10-1.51). In subgroup analysis, we observed a significant association between rs2296545 and risk of essential HT. Although we did not observe an association between rs2576178 polymorphism and HT in the combined analysis, an increased risk was observed in the essential HT patients versus healthy controls (subgroup 1) analysis under the dominant, recessive, and codominant genetic models. CONCLUSIONS: Renalase gene rs2296545 polymorphism is significantly associated with increased risk of HT, whereas rs2576178 polymorphism may not be associated with the susceptibility to HT.

Elevation of Fasting Ghrelin in Healthy Human Subjects Consuming a High-Salt Diet: A Novel Mechanism of Obesity?

Overweight/obesity is a chronic disease that carries an increased risk of hypertension, diabetes mellitus, and premature death. Several epidemiological studies have demonstrated a clear relationship between salt intake and obesity, but the pathophysiologic mechanisms remain unknown. We hypothesized that ghrelin, which regulates appetite, food intake, and fat deposition, becomes elevated when one consumes a high-salt diet, contributing to the progression of obesity. We, therefore, investigated fasting ghrelin concentrations during a high-salt diet. Thirty-eight non-obese and normotensive subjects (aged 25 to 50 years) were selected from a rural community in Northern China. They were sequentially maintained on a normal diet for three days at baseline, a low-salt diet for seven days (3 g/day, NaCl), then a high-salt diet for seven days (18 g/day). The concentration of plasma ghrelin was measured using an immunoenzyme method (ELISA). High-salt intake significantly increased fasting ghrelin levels, which were higher during the high-salt diet (320.7 ± 30.6 pg/mL) than during the low-salt diet (172.9 ± 8.9 pg/mL). The comparison of ghrelin levels between the different salt diets was statistically-significantly different (p < 0.01). A positive correlation between 24-h urinary sodium excretion and fasting ghrelin levels was demonstrated. Our data indicate that a high-salt diet elevates fasting ghrelin in healthy human subjects, which may be a novel underlying mechanism of obesity.

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.

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.

High-salt intake suppressed microRNA-133a expression in Dahl SS rat myocardium.

Salt-sensitive individuals show earlier and more serious cardiac damage than nonsalt-sensitive ones. Some studies have suggested that microRNA-133a could reduce cardiac hypertrophy and myocardial fibrosis. The current study aims to investigate the different functions of high-salt intake on salt-sensitive (SS) rats and Sprague-Dawley (SD) rats and the involvement of microRNA-133a in these roles. After high-salt intervention, the left ventricular mass (LVW) and left ventricular mass index (LVMI) of the salt-sensitive high salt (SHS) group were obviously higher than those of the salt-sensitive low salt (SLS) group. However, the difference between the Sprague-Dawley high salt (DHS) group and the Sprague-Dawley low salt (DLS) group was not significant. Compared with SLS group, collagen I and connective tissue growth factor (CTGF) in the heart of SHS group were significantly higher, whereas no statistical difference was observed between the DHS group and the DLS group. Compared with low-salt diet, microRNA-133a in the heart of both strains were significantly decreased, but that in the SHS group decreased more significantly. These results suggest that high salt intervention could down-regulate the expression of myocardial microRNA-133a, which may be one of the mechanisms involved in myocardial fibrosis in salt-sensitive hypertension.