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BACKGROUND: The mTOR (mechanistic target of rapamycin) is an essential regulator of fundamental biological processes. mTOR forms 2 distinct complexes, mTORC1 (mTOR complex 1) when it binds with RAPTOR (Regulatory-associated Protein of mTOR) and mTORC2 (mTOR complex 2) when it associates with RICTOR (Rapamycin-insesitive companion of mTOR). Due to the previous link between the mTOR pathway, aldosterone, and blood pressure (BP), we anticipated that variants in the mTOR complex might be associated with salt-sensitive BP. METHODS: BP and other parameters were assessed after a one-week liberal Na+ (200 mmol/d) and a one-week restricted Na+ (10 mmol/d) diet in 608 White subjects from the Hypertensive Pathotype cohort, single-nucleotide variants in MTOR , RPTOR , and RICTOR genes were obtained for candidate genes analyses. RESULTS: The analysis revealed a significant association between a single nucleotide variants within the RPTOR gene and BP. Individuals carrying the RPTOR rs9901846 homozygous risk allele (AA) and heterozygous risk allele (GA) exhibited a 5 mm Hg increase in systolic BP on a liberal diet compared with nonrisk allele individuals (GG), but only in women. This single nucleotide variants effect was more pronounced on the restricted diet and present in both sexes, with AA carriers having a 9 mm Hg increase and GA carriers having a 5 mm Hg increase in systolic BP compared with GG. Interestingly, there were no significant associations between MTOR or RICTOR gene variants and BP. CONCLUSIONS: The RPTOR gene variation is associated with elevated BP in White participants, regardless of salt intake, specifically in females. [ABSTRACT FROM AUTHOR]

BACKGROUND: Salt sensitivity of blood pressure (SSBP) is a substantial risk factor for cardiovascular morbidity and mortality. Striatin (STRN) is critical for estrogen and aldosterone nongenomic signaling. However, the role of biological sex on the SSBP phenotype associated with STRN gene variants remains unexplored. METHOD: Data from 1306 subjects participating in the Hypertensive Pathotype (HyperPATH) Consortium were used to identify STRN gene single-nucleotide variants associated with SSBP. Haploblock analysis revealed a novel diplotype in the upstream regulatory region of STRN (rs888083 and rs6744560), with 31% of subjects being homozygous for the risk diplotype. RESULTS: Individuals homozygous for the risk diplotype had significantly greater SSBP than nonrisk diplotypes (P<0.009). While a significant genotype/SSBP association was present in both sexes, their potential mechanisms differed. Women, but not men homozygous risk diplotypes, had significantly greater aldosterone levels than nonrisk diplotypes (5.8±0.4 versus 3.2±0.7 ng/dl; P=0.01; liberal Na+ diet, adjusted). Men, but not women, homozygous risk diplotypes, had significantly reduced renal plasma flow response to Angiotensin II than nonrisk diplotypes (delta 95.2±5.2 versus 122.9±10.2 mL/min per 1.73 m²; P=0.01; liberal Na+ diet, adjusted). The single-nucleotide variants composing the risk diplotype were associated with lower STRN mRNA expression in human tissues (in silico). CONCLUSION: In women, the primary driver of SSBP is increased aldosterone, while in men, it is reduced renal plasma flow responses. Thus, despite a common hypertensive phenotype (SSBP) in both sexes, the specific treatment approaches might differ to increase therapeutic gain and mitigate adverse effects. These genetic- and sex-based observational results require confirmation in a prospective clinical study. [ABSTRACT FROM AUTHOR]

BACKGROUND: Disease-causing mutations in CACNA1D gene occur in aldosterone-producing adenomas and familial hyperaldosteronism. We determined whether single nucleotide polymorphisms in CACNA1D gene associate with higher aldosterone resulting in salt sensitivity of blood pressure (BP) and increased BP in men and women. METHODS: Data were obtained from the HyperPATH (International Hypertension Pathotypes) cohort, where participants completed a cross-over intervention of liberal and restricted sodium diets. Multi-Ethnic Genotyping Array identified 104 CACNA1D single nucleotide polymorphisms that met quality control. Single nucleotide polymorphism is rs7612148 strongly associated with systolic BP and was selected for study in 521 White participants in 3 scenarios ([1] hypertensives; [2] normotensives; [3] total population=hypertensives+normotensives) using multivariate regression analysis. RESULTS: In the total population and hypertensives, but not normotensives, risk allele carriers (CC, GC), as compared with nonrisk allele homozygotes (GG), exhibited higher salt sensitivity of BP and, on liberal sodium diet, higher systolic BP, lower baseline and angiotensin II-stimulated aldosterone, and lower plasma renin activity. On restricted sodium diet, BP was similar across genotypes, suggesting sodium restriction corrected/neutralized the genotype effect on BP. Because increased aldosterone did not seem to drive the increased salt sensitivity of BP and increased BP on liberal sodium diet, we assessed renal plasma flow. Renal plasma flow increase from restricted to liberal sodium diets was blunted in risk allele homozygotes in the total population and in hypertensives. A replication study in another cohort HyperPATH B (International Hypertension Pathotypes Cohort B) confirmed BP-genotype associations. CONCLUSIONS: CACNA1D rs7612148 risk allele associated with increased BP and salt sensitivity of BP, likely due to an impaired ability to increase renal plasma flow in response to a liberal sodium diet and not to excess aldosterone. [ABSTRACT FROM AUTHOR]

[Figure: see text]. [ABSTRACT FROM AUTHOR]

Background and Purpose: The instrumented Timed Up and Go test (iTUG) affords quantification of the subelements of the Timed Up and Go test to assess fall risk and physical performance. A miniature sensor applied to the back is able to capture accelerations and velocities from which the subelements of the iTUG can be quantified. This study is the first to compare iTUG performance between people with dementia (PWD) and their age-matched caregivers. The aims of this study were to explore how age moderates the differences in performance on the iTUG between PWD and their informal caregivers. Methods: Eight-three community-dwelling older PWD and their informal caregivers were recruited for this cross-sectional, observational study. Participants were grouped by age: younger than 70 years, 70 to 79 years, and 80 years and older. Participants wore an inertial sensor while performing the iTUG in their home. The performance of the subelements sit-to-stand, walking, and turning were captured through an algorithm converting accelerations and velocities into performance metrics such as duration and peak velocity. Performance for PWD was compared with caregivers for each age-matched group, and multiple regression models incorporating age, gender, and presence or absence of dementia were computed. Results: People with dementia took longer to turn in the younger than 70-year group, suggesting this may be an early indicator of functional decline in this age group. People with dementia took longer to complete the whole iTUG compared with caregivers in the 70- to 79-year-old group. In the 80+-year-old group, PWD took longer to complete both walking phases, sit-to-stand, and the full iTUG along with displaying slower turning velocity. Multiple regression models illustrated that gender failed to contribute significantly to the model, but age and presence of dementia explained around 30% of the variance of time to complete walking phases, total iTUG, and turning velocity. Conclusions: Differences were evident in performance of the iTUG between PWD and caregivers even after controlling for age. Age moderates the differences observed in performance. [ABSTRACT FROM AUTHOR]

Statin use is associated with lower aldosterone levels. We hypothesized that caveolin-1 may be important for the uptake of statins into the adrenal gland and would affect statin's aldosterone-lowering effects. The aim of this study was to test whether the caveolin-1 risk allele (rs926198) would affect aldosterone levels associated with statin use. The Hypertensive Pathotype database includes healthy and hypertensive individuals who have undergone assessment of adrenal hormones. Individuals were studied off antihypertensive medications but were maintained on statins if prescribed by their personal physician. Adrenal hormones were measured at baseline and after 1 hour of angiotensin II stimulation on both high- and low-sodium diets. A mixed-model repeated-measures analysis was employed with a priori selected covariates of age, sex, body mass index, and protocol (low versus high sodium, baseline versus angiotensin II stimulated aldosterone). A total of 250 individuals were included in the study; 31 individuals were taking statins (12.4%) and 219 were not. Among statin users, carrying a caveolin-1 risk allele resulted in a 25% (95% CI, 1-43.2) lower aldosterone level (P=0.04). However, among nonstatin users, carrying a caveolin-1 risk allele resulted in no significant effect on aldosterone levels (P=0.38). Additionally, the interaction between caveolin-1 risk allele and statin use on aldosterone levels was significant (P=0.03). These findings suggest caveolin-1 risk allele carrying individuals are likely to receive the most benefit from statin's aldosterone-lowering properties; however, due to the observational nature of this study, these findings need further investigation. [ABSTRACT FROM AUTHOR]

LSD1 (lysine-specific demethylase-1) is an epigenetic regulator of gene transcription. LSD1 risk allele in humans and LSD1 deficiency (LSD1+/-) in mice confer increasing salt-sensitivity of blood pressure with age, which evolves into salt-sensitive hypertension in older individuals. However, the mechanism underlying the relationship between LSD1 and salt-sensitivity of blood pressure remains elusive. Here, we show that LSD1 genotype (in humans) and LSD1 deficiency (in mice) lead to similar associations with increased blood pressure and urine potassium levels but with decreased aldosterone levels during a liberal salt diet. Thus, we hypothesized that LSD1 deficiency leads to an MR (mineralocorticoid receptor)-dependent hypertensive state. Yet, further studies in LSD1+/- mice treated with the MR antagonist eplerenone demonstrate that hypertension, kaliuria, and albuminuria are substantially improved, suggesting that the ligand-independent activation of the MR is the underlying cause of this LSD1 deficiency-mediated phenotype. Indeed, while MR and epithelial sodium channel expression levels were increased in LSD1+/- mouse kidney tissues, aldosterone secretion from LSD1+/- glomerulosa cells was significantly lower. Collectively, these data establish that LSD1 deficiency leads to an inappropriate activation and increased levels of the MR during a liberal salt regimen and suggest that inhibiting the MR pathway is a useful strategy for treatment of hypertension in human LSD1 risk allele carriers. [ABSTRACT FROM AUTHOR]

We have previously reported that in salt-resistant rat phenotypes brain, Gαi2 (guanine nucleotide-binding protein alpha inhibiting activity polypeptide 2) proteins are required to maintain blood pressure and sodium balance. However, the impact of hypothalamic paraventricular nucleus (PVN) Gαi2 proteins on the salt sensitivity of blood pressure is unknown. Here, by the bilateral PVN administration of a targeted Gαi2 oligodeoxynucleotide, we show that PVN-specific Gαi2 proteins are required to facilitate the full natriuretic response to an acute volume expansion (peak natriuresis [μeq/min] scrambled (SCR) oligodeoxynucleotide 41±3 versus Gαi2 oligodeoxynucleotide 18±4; P<0.05) via a renal nerve-dependent mechanism. Furthermore, in response to chronically elevated dietary sodium intake, PVN-specific Gαi2 proteins are essential to counter renal nerve-dependent salt-sensitive hypertension (mean arterial pressure [mm Hg] 8% NaCl; SCR oligodeoxynucleotide 128±2 versus Gαi2 oligodeoxynucleotide 147±3; P<0.05). This protective pathway involves activation of PVN Gαi2 signaling pathways, which mediate sympathoinhibition to the blood vessels and kidneys (renal norepinephrine [pg/mg] 8% NaCl; SCR oligodeoxynucleotide 375±39 versus Gαi2 oligodeoxynucleotide 850±27; P<0.05) and suppression of the activity of the sodium chloride cotransporter assessed as peak natriuresis to hydrochlorothiazide. Additionally, central oligodeoxynucleotide-mediated Gαi2 protein downregulation prevented PVN parvocellular neuron activation, assessed by FosB immunohistochemistry, in response to increased dietary salt intake. In our analysis of the UK BioBank data set, it was observed that 2 GNAI2 single nucleotide polymorphism (SNP) (rs2298952, P=0.041; rs4547694, P=0.017) significantly correlate with essential hypertension. Collectively, our data suggest that selective targeting and activation of PVN Gαi2 proteins is a novel therapeutic approach for the treatment of salt-sensitive hypertension. [ABSTRACT FROM AUTHOR]

The SPRINT (Systolic Blood Pressure Intervention Trial) demonstrated reduced cardiovascular outcomes. We evaluated diabetes mellitus incidence in this randomized trial that compared intensive blood pressure strategy (systolic blood pressure <120 mm Hg) versus standard strategy (<140 mm Hg). Participants were ≥50 years of age, with systolic 130 to 180 mm Hg and increased cardiovascular risk. Participants were excluded if they had diabetes mellitus, polycystic kidney disease, proteinuria >1 g/d, heart failure, dementia, or stroke. Postrandomization exclusions included participants missing blood glucose or ≥126 mg/dL (6.99 mmol/L) or on hypoglycemics. The outcome was incident diabetes mellitus: fasting blood glucose ≥126 mg/dL (6.99 mmol/L), diabetes mellitus self-report, or new use of hypoglycemics. The secondary outcome was impaired fasting glucose (100-125 mg/dL [5.55-6.94 mmol/L]) among those with normoglycemia (<100 mg/dL [5.55 mmol/L]). There were 9361 participants randomized and 981 excluded, yielding 4187 and 4193 participants assigned to intensive and standard strategies. There were 299 incident diabetes mellitus events (2.3% per year) for intensive and 251 events (1.9% per year) for standard, rates of 22.6 (20.2-25.3) versus 19.0 (16.8-21.5) events per 1000 person-years of treatment, respectively (adjusted hazard ratio, 1.19 [95% CI, 0.95-1.49]). Impaired fasting glucose rates were 26.4 (24.9-28.0) and 22.5 (21.1-24.1) per 100 person-years for intensive and standard strategies (adjusted hazard ratio, 1.17 [1.06-1.30]). Intensive treatment strategy was not associated with increased diabetes mellitus but was associated with more impaired fasting glucose. The risks and benefits of intensive blood pressure targets should be factored into individualized patient treatment goals. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT01206062. [ABSTRACT FROM AUTHOR]

The relationship between biological sex and aldosterone on blood pressure (BP) is unclear. We hypothesized that sex would modify the interaction between aldosterone and vascular responses to salt intake and angiotensin II (AngII). To test this hypothesis, in 1592 subjects from the well-controlled Hypertensive Pathotype cohort, we compared responses of women and men to chronic (BP and aldosterone levels in response to dietary salt) and acute (BP, renal plasma flow, and aldosterone responses to AngII infusion) manipulations. Women had a 30% higher salt sensitivity of BP than men (P<0.0005) regardless of age or hypertension status, a greater BP response to AngII, and a 15% greater aldosterone response to AngII on both restricted and liberal salt diets (P<0.005). Furthermore, there was an interaction (P=0.003) between sex and aldosterone on BP response to AngII. Women also had a greater (P<0.01) increment in renal plasma flow in response to AngII than men. To assess potential mechanisms for this sex effect, we compared aldosterone responses to AngII or potassium from rat zona glomerulosa cells and observed greater aldosterone production in female than male zona glomerulosa cells basally and in response to both agonists (P<0.0001). In a rodent model of aldosterone-mediated cardiovascular disease induced by increased AngII and low NO, circulating aldosterone levels (P<0.01), myocardial damage (P<0.001), and proteinuria (P<0.05) were greater in female than male rats despite having similar BP responses. Thus, increased aldosterone production likely contributes to sex differences in cardiovascular disease, suggesting that women may be more responsive to mineralocorticoid receptor blockade than men. [ABSTRACT FROM AUTHOR]

Striatin is a novel protein that interacts with steroid receptors and modifies rapid, nongenomic activity in vitro. We tested the hypothesis that striatin would in turn affect mineralocorticoid receptor function and consequently sodium, water, and blood pressure homeostasis in an animal model. We evaluated salt sensitivity of blood pressure in novel striatin heterozygote knockout mice. Compared with wild type, striatin heterozygote exhibited a significant increase in blood pressure when sodium intake was increased from restricted (0.03%) to liberal (1.6%) sodium. Furthermore, renal expression of mineralocorticoid receptor and its genomic downstream targets serum/glucocorticoid-regulated kinase 1, and epithelial sodium channel was increased in striatin heterozygote versus wild-type mice on liberal sodium intake while the pAkt/Akt ratio, readout of mineralocorticoid receptor's rapid, nongenomic pathway, was reduced. To determine the potential clinical relevance of these findings, we tested the association between single nucleotide polymorphic variants of striatin gene and salt sensitivity of blood pressure in 366 white hypertensive subjects. HapMap-derived tagging single nucleotide polymorphisms identified an association of rs2540923 with salt sensitivity of blood pressure (odds ratio, 6.25; 95% confidence interval, 1.7-20; P=0.01). These data provide the first in vivo evidence in humans and rodents that associates striatin with markers of mineralocorticoid receptor activity. The data also support the hypothesis that the rapid, nongenomic mineralocorticoid receptor pathway (mediated via striatin) has a role in modulating the interaction between salt intake and blood pressure. [ABSTRACT FROM AUTHOR]

Accumulating evidence shows an increase in insulin resistance on salt restriction. We compared the effect of low salt diet on insulin resistance in salt-sensitive versus salt-resistant hypertensive subjects. We also evaluated the relationship between salt sensitivity of blood pressure and salt sensitivity of insulin resistance in a multivariate regression model. Studies were conducted after 1 week of high salt (200 mmol per day sodium) and 1 week of low salt (10 mmol per day sodium) diet. Salt sensitivity was defined as the fall in systolic blood pressure >15 mm Hg on low salt diet. The study includes 389 subjects (44% women; 16% blacks; body mass index, 28.5±4.2 kg/m²). As expected, blood pressure was lower on low salt (129±16/78±9 mm Hg) as compared with high salt diet (145±18/86±10 mm Hg). Fasting plasma glucose, insulin, and homeostasis model assessment were higher on low salt diet (95.4±19.4 mg/dL; 10.8±7.3 mIU/L; 2.6±1.9) as compared with high salt diet (90.6±10.8 mg/dL; 9.4±5.8 mIU/L; 2.1±1.4; P<0.0001 for all). There was no difference in homeostasis model assessment between salt-sensitive (n=193) versus salt-resistant (n=196) subjects on either diet. Increase in homeostasis model assessment on low salt diet was 0.5±1.4 in salt-sensitive and 0.4±1.5 in salt- resistant subjects (P=NS). On multivariate regression analysis, change in systolic blood pressure was not associated with change in homeostasis model assessment after including age, body mass index, sex, change in serum and urine aldosterone, and cortisol into the model. We conclude that the increase in insulin resistance on low salt diet is not affected by salt sensitivity of blood pressure. [ABSTRACT FROM AUTHOR]

Observational studies in primary hyperaldosteronism suggest a positive relationship between aldosterone and parathyroid hormone (PTH); however, interventions to better characterize the physiological relationship between the renin--angiotensin-aldosterone system (RAAS) and PTH are needed. We evaluated the effect of individual RAAS components on PTH using 4 interventions in humans without primary hyperaldosteronism. PTH was measured before and after study (1) low-dose angiotensin II (Ang II) infusion (1 ng/kg per minute) and captopril administration (25 mgx1); study (2) high-dose Ang II infusion (3 ng/kg per minute); study (3) blinded crossover randomization to aldosterone infusion (0.7 µg/kg per hour) and vehicle; and study (4) blinded randomization to spironolactone (50 mg/daily) or placebo for 6 weeks. Infusion of Ang II at 1 ng/kg per minute acutely increased aldosterone (+148%) and PTH (+10.3%), whereas Ang II at 3 ng/kg per minute induced larger incremental changes in aldosterone (+241%) and PTH (+36%; P<0.01). Captopril acutely decreased aldosterone (-12%) and PTH (-9.7%; P<0.01). In contrast, aldosterone infusion robustly raised serum aldosterone (+892%) without modifying PTH. However, spironolactone therapy during 6 weeks modestly lowered PTH when compared with placebo (P<0.05). In vitro studies revealed the presence of Ang II type I and mineralocorticoid receptor mRNA and protein expression in normal and adenomatous human parathyroid tissues. We observed novel pleiotropic relationships between RAAS components and the regulation of PTH in individuals without primary hyperaldosteronism: the acute modulation of PTH by the RAAS seems to be mediated by Ang II, whereas the long-term influence of the RAAS on PTH may involve aldosterone. Future studies to evaluate the impact of RAAS inhibitors in treating PTH-mediated disorders are warranted. [ABSTRACT FROM AUTHOR]

The article examines whether single nucleotide polymorphisms (SNPs) in sodium-bicarbonate co-transporter gene (SLC4A5) are associated with salt sensitivity of blood pressure in 185 whites. The subjects consumed an isocaloric constant diet with a randomized order of 7 days of low Na+ and 7 days of high Na+ intake. SLC4A5 variants are strongly associated with salt sensitivity of blood pressure in 2 separate white populations.

Vitamin D regulates the renin-angiotensin system (RAS) in experimental animals, but corresponding human data are limited. We examined the relation between plasma 25-hydroxyvitamin D and elements of the RAS in 184 normotensive individuals in high sodium balance; these included circulating levels of plasma renin activity and angiotensin II (Ang II) and the renal plasma flow response to infused Ang II, which is an indirect measure of the intrinsic RAS activity in the kidney. Compared with individuals with sufficient 25-hydroxyvitamin D levels (> or = 30.0 ng/mL), those with insufficiency (15.0 to 29.9 ng/mL) and deficiency (<15.0 ng/mL) had higher circulating Ang II levels (P for trend=0.03). Moreover, those with vitamin D deficiency had significantly blunted renal plasma flow responses to infused Ang II (mean decrease of 115 mL/min per 1.73 m(2) in renal plasma flow versus 145 mL/min per 1.73 m(2) among those with sufficient vitamin D levels; P for trend=0.009). Although plasma renin activity was higher among individuals with insufficient levels of vitamin D, the result was not statistically significant. These data suggest that low plasma 25-hydroxyvitamin D levels may result in upregulation of the RAS in otherwise healthy humans. [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests that genes of the hypothalamic-pituitary-thyroid pathway influence susceptibility to hypertension. Type 2 iodothyronine deiodinase is responsible for the conversion of thyroxine to tri-iodothyronine for use in peripheral tissues. The present study evaluated whether a type 2 iodothyronine deiodinase nonsynonymous polymorphism, threonine 92 to alanine (Thr92Ala), is a determinant of hypertension susceptibility. A total of 372 euthyroid subjects were genotyped for Thr92Ala polymorphism using the Sequenom MassARRAY platform. Associations with hypertension and hypertension-related intermediate phenotypes were performed with generalized estimating equations. Type 2 iodothyronine deiodinase Thr92Ala allele frequencies differed significantly between hypertensive and normotensive subjects, with an excess of Ala92 carriers in hypertensive compared with normotensive subjects (64.8% versus 47.1%; P=0.011). Adjusted for age, gender and race, the estimated odds ratio for hypertension in Ala92 allele carriers compared with Thr92 homozygotes was 2.11 (95% CI: 1.15 to 3.89). Among euthyroid adults, the common Ala92 allele of the type 2 iodothyronine deiodinase increases risk for the development of hypertension. These data support an important role for genetic variation in the hypothalamic-pituitary-thyroid pathway in influencing susceptibility to hypertension. [ABSTRACT FROM AUTHOR]

Introduction: Retinol-binding protein 4 (RBP-4) is a circulating adipokine associated with insulin resistance, obesity and cardiovascular risk. Previous evidence suggests a negative impact on insulin sensitivity via an interaction with the insulin-stimulated glucose transporter (GLUT-4), specifically in adipocytes. Since angiotensin-2 (ANG-2) impairs GLUT-4 presentation and insulin sensitivity, we hypothesized that renin-angiotensin system (RAS) activity might affect RBP-4 expression as well. Furthermore, both RAS activity and insulin sensitivity are affected by dietary salt, but the relationship between these factors and RBP-4 expression is unknown. We hypothesized that liberal salt diet, via suppression of RAS activity, would be associated with reduced RBP-4 levels compared to salt restriction.METHODS: Healthy subjects (7 men, 7 women, mean age 24 yr, BMI 22.6) were studied on low salt (LS 10 mmol Na/day) diet and then liberal salt (HS 200 mmol Na/day) diet for 1 week each. Samples were drawn after overnight rest in the supine position for plasma renin activity (PRA), serum Aldosterone (Aldo) and plasma RBP-4 and again after ANG-2 infusion (3ng/kg/min x 45 mins).Results: Salt manipulation predictably modified RAS activity (HS v. LS Aldo, 4.5 ± 3.8 v. 19.5 ± 8.5 ng/dl [p<0.01]; HS v. LS PRA, 0.5 ± 0.4 v. 2.7 ± 1.4 ng/ml/hr [p<0.01]). RBP-4 was significantly lower on a HS compared to LS diet (35.4 ± 6.6 v. 38.6 ± 7.9 mg/L, p= 0.017). No significant change was observed in RBP-4 level after ANG-2 infusion on either diet. Fasting insulin levels trended lower on HS compared to LS (3.9 ± 6.8 v. 4.4 ± 1.2 μIU/ml, p=0.09), but there was no difference in fasting glucose (81.9 ± 6.8 v. 82.1 ± 4.7 mg/dl, p=0.92).Conclusion: RBP-4 levels are modified by dietary salt intake. RBP-4 levels were lower under HS conditions (suppressed RAS) as compared to LS conditions. Acute administration of ANG-2 does not increase RBP-4 levels in this healthy population. Insulin response was similar to prior reports suggesting that the connection between RAS activity, dietary salt and insulin sensitivity may include RBP-4. Future work exploring the relationship between RBP-4, GLUT-4 and insulin sensitivity should take into consideration the effect of dietary salt intake. [ABSTRACT FROM AUTHOR]

Studies have reported an association of angiotensinogen (AGT) gene polymorphisms with hypertension and renal blood flow (RBF). The T allele of rs699 (AGT 235T) is associated with increased levels of angiotensinogen and reduced RBF. Plasminogen activator inhibitor-1 (PAI-1) is an inhibitor of the fibrinolytic pathway. Elevated PAI-1 is associated with increased renin-angiotensin system (RAS) activity and cardiovascular damage. We hypothesized that hypertensive individuals with the TT genotype of AGT 235 would display higher levels of PAI-1. We further hypothesized an inverse relationship would be observed between PAI-1 and RBF, and that the strength of this correlation would be dependent on genotype status. A total of 159 Caucasian hypertensive participants (mean age 49.3y, BMI 27.6) had data available for AGT235, PAI-1 and RBF from the HyperPATH study. RBF was measured by para-aminohippurate clearance method while on a liberal salt diet (>200 mmol Na/day for 1 week). Genotype frequencies were in Hardy-Weinberg Equilibrium (MM 41/MT 94/TT 24). Multivariate regression demonstrated the TT genotype was associated with higher PAI-1 levels compared with MT + MM (41.0±8.1 v. 26.9±7.1ng/ml, p=0.005). Genotype status modified the relationship between PAI-1 and RBF whereby only the TT genotype showed a significant correlation after adjusting for age, BMI and BP (TT pr2=0.22, Beta= -1.66 p=0.001 v. MT+MM pr2=0.05, Beta= -0.82, p=0.21). AGT 235T is associated with elevated PAI-1 and influences the relationship between PAI-1 and RBF in Caucasian hypertensives. This provides mechanistic clues to explain the genetic underpinnings involving AGT polymorphisms and hypertension. [ABSTRACT FROM AUTHOR]