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1.
Expert Rev Cardiovasc Ther ; 22(6): 265-271, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38823009

ABSTRACT

INTRODUCTION: The aim of the present study is to analyze the data indicating an association between high salt intake and the gastrointestinal microbiota in the development of salt-sensitive hypertension in animals and men. It is also, to discuss the preventive effects of exercise on gut-induced hypertension by favorably modifying the composition of gut microbiota. AREAS COVERED: Salt sensitivity is quite common, accounting for 30%-60% in hypertensive subjects. Recently, a novel cause for salt-sensitive hypertension has been discovered through the action of gut microbiota by the secretion of several hormones and the action of short chain fatty acids (SCFAs). In addition, recent studies indicate that exercise might favorably modify the adverse effects of gut microbiota regarding their effects on BP. To identify the role of gut microbiota on the incidence of hypertension and CVD and the beneficial effect of exercise, a Medline search of the English literature was conducted between 2018 and 2023 and 42 pertinent papers were selected. EXPERT OPINION: The analysis of data from the selected papers disclosed that the gut microbiota contribute significantly to the development of salt-sensitive hypertension and that exercise modifies their gut composition and ameliorates their adverse effects on BP.


Subject(s)
Blood Pressure , Exercise , Gastrointestinal Microbiome , Hypertension , Sodium Chloride, Dietary , Gastrointestinal Microbiome/physiology , Humans , Hypertension/prevention & control , Sodium Chloride, Dietary/adverse effects , Sodium Chloride, Dietary/administration & dosage , Animals , Exercise/physiology , Fatty Acids, Volatile/metabolism
2.
Cells ; 13(11)2024 May 25.
Article in English | MEDLINE | ID: mdl-38891044

ABSTRACT

Several chronic inflammatory diseases have been linked to high-salt (HS) diets. Chronic inflammation is an established causative hallmark of cancer. However, a direct role of HS diets in tumorigenesis is yet to be defined. Previous orthotopic murine breast tumor studies have shown that short-term HS diets caused inhibition of tumor growth through the activation of cytotoxic adaptive immune responses. However, there have been experimental challenges in developing a viable chronic HS-diet-based murine tumor model. To address this, we have developed a novel chronic HS diet tumor model through the sequential passaging of tumor cells in mice under HS dietary conditions. Two orthotopic murine triple-negative breast cancer models, 4T1 tumor cells injected into BALB/c mice and Py230 tumor cells injected into C57Bl/6 mice, were utilized in our study. For the HS diet cohort, prior to orthotopic injection with tumor cells, the mice were kept on a 4% NaCl diet for 2 weeks. For the regular salt (RS) diet cohort, the mice were kept on a 1% NaCl diet. Following syngeneic cancer cell injection, tumors were allowed to grow for 28 days, following which they were collected to isolate immune cell-depleted cancer cells (passage 1, P1). The tumor cells from P1 were reinjected into the next set of non-tumor-bearing mice. This procedure was repeated for three cycles (P2-P4). In P1, compared to the RS diet cohort, we observed reduced tumor kinetics in both murine tumor models on the HS diet. In contrast, by P4, there was significantly higher tumor progression in the HS diet cohort over the RS diet cohort. Flow cytometry analysis demonstrated an 8-fold increase in tumor-initiating stem cells (TISCs) from P1 to P4 of the HS diet cohort, while there were no significant change in TISC frequency with sequential passaging in the RS diet cohort. Molecular studies showed enhanced expression of TGFßR2 and CD80 on TISCs isolated from the P4 HS diet cohort. In vitro studies demonstrated that TGFß stimulation of these TISCs increased the cellular expression of CD80 molecules. Further, the chronic HS diet selectively induced the glycolytic metabolic phenotype over the mitochondrial oxidative phosphorylation phenotype in TISCs, which is needed for the production of metabolites during tumor cell differentiation and proliferation. The infiltrating CD8 and CD4 T-lymphocytes in P4 tumors demonstrated increased expression of the immune checkpoint inhibitor (ICI) CTLA4, a known binding partner of CD80, to cause immune exhaustion and pro-tumorigenic effects. Interestingly, anti-TGFß monoclonal antibodies (mAbs) played a synergistic role in further enhancing the anti-tumor effect of anti-CTLA4 mAb. In summary, our findings demonstrated that chronic HS diet increased the frequency of TISCs in tumors leading to blunting of cytotoxic adaptive immune responses causing tumor proliferation. Furthermore, a combination of anti-TGFß with current ICI-based immunotherapies could exert more favorable anti-cancer clinical outcomes.


Subject(s)
Cell Proliferation , Mice, Inbred BALB C , Neoplastic Stem Cells , Animals , Female , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Cell Proliferation/drug effects , Mice , Cell Line, Tumor , Breast Neoplasms/pathology , Breast Neoplasms/metabolism , Sodium Chloride, Dietary/adverse effects , Mice, Inbred C57BL , Humans
3.
BMC Genomics ; 25(1): 612, 2024 Jun 18.
Article in English | MEDLINE | ID: mdl-38890564

ABSTRACT

BACKGROUND: Salt sensitivity of blood pressure (SSBP) is an intermediate phenotype of hypertension and is a predictor of long-term cardiovascular events and death. However, the genetic structures of SSBP are uncertain, and it is difficult to precisely diagnose SSBP in population. So, we aimed to identify genes related to susceptibility to the SSBP, construct a risk evaluation model, and explore the potential functions of these genes. METHODS AND RESULTS: A genome-wide association study of the systemic epidemiology of salt sensitivity (EpiSS) cohort was performed to obtain summary statistics for SSBP. Then, we conducted a transcriptome-wide association study (TWAS) of 12 tissues using FUSION software to predict the genes associated with SSBP and verified the genes with an mRNA microarray. The potential roles of the genes were explored. Risk evaluation models of SSBP were constructed based on the serial P value thresholds of polygenetic risk scores (PRSs), polygenic transcriptome risk scores (PTRSs) and their combinations of the identified genes and genetic variants from the TWAS. The TWAS revealed that 2605 genes were significantly associated with SSBP. Among these genes, 69 were differentially expressed according to the microarray analysis. The functional analysis showed that the genes identified in the TWAS were enriched in metabolic process pathways. The PRSs were correlated with PTRSs in the heart atrial appendage, adrenal gland, EBV-transformed lymphocytes, pituitary, artery coronary, artery tibial and whole blood. Multiple logistic regression models revealed that a PRS of P < 0.05 had the best predictive ability compared with other PRSs and PTRSs. The combinations of PRSs and PTRSs did not significantly increase the prediction accuracy of SSBP in the training and validation datasets. CONCLUSIONS: Several known and novel susceptibility genes for SSBP were identified via multitissue TWAS analysis. The risk evaluation model constructed with the PRS of susceptibility genes showed better diagnostic performance than the transcript levels, which could be applied to screen for SSBP high-risk individuals.


Subject(s)
Blood Pressure , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Blood Pressure/genetics , Gene Expression Profiling , Hypertension/genetics , Transcriptome , Polymorphism, Single Nucleotide , Male , Risk Assessment , Female , Sodium Chloride, Dietary/adverse effects
4.
Int J Mol Sci ; 25(10)2024 May 18.
Article in English | MEDLINE | ID: mdl-38791545

ABSTRACT

Hypertension stands as the leading global cause of mortality, affecting one billion individuals and serving as a crucial risk indicator for cardiovascular morbidity and mortality. Elevated salt intake triggers inflammation and hypertension by activating antigen-presenting cells (APCs). We found that one of the primary reasons behind this pro-inflammatory response is the epithelial sodium channel (ENaC), responsible for transporting sodium ions into APCs and the activation of NADPH oxidase, leading to increased oxidative stress. Oxidative stress increases lipid peroxidation and the formation of pro-inflammatory isolevuglandins (IsoLG). Long noncoding RNAs (lncRNAs) play a crucial role in regulating gene expression, and MALAT1, broadly expressed across cell types, including blood vessels and inflammatory cells, is also associated with inflammation regulation. In hypertension, the decreased transcriptional activity of nuclear factor erythroid 2-related factor 2 (Nrf2 or Nfe2l2) correlates with heightened oxidative stress in APCs and impaired control of various antioxidant genes. Kelch-like ECH-associated protein 1 (Keap1), an intracellular inhibitor of Nrf2, exhibits elevated levels of hypertension. Sodium, through an increase in Sp1 transcription factor binding at its promoter, upregulates MALAT1 expression. Silencing MALAT1 inhibits sodium-induced Keap1 upregulation, facilitating the nuclear translocation of Nrf2 and subsequent antioxidant gene transcription. Thus, MALAT1, acting via the Keap1-Nrf2 pathway, modulates antioxidant defense in hypertension. This review explores the potential role of the lncRNA MALAT1 in controlling the Keap1-Nrf2-antioxidant defense pathway in salt-induced hypertension. The inhibition of MALAT1 holds therapeutic potential for the progression of salt-induced hypertension and cardiovascular disease (CVD).


Subject(s)
Hypertension , RNA, Long Noncoding , Animals , Humans , Gene Expression Regulation , Hypertension/genetics , Hypertension/metabolism , Hypertension/etiology , Kelch-Like ECH-Associated Protein 1/metabolism , Kelch-Like ECH-Associated Protein 1/genetics , NF-E2-Related Factor 2/metabolism , NF-E2-Related Factor 2/genetics , Oxidative Stress , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Sodium Chloride, Dietary/adverse effects
6.
Hypertension ; 81(7): 1511-1523, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38757269

ABSTRACT

BACKGROUND: It is established that the immune system, namely T cells, plays a role in the development of hypertension and renal damage in male Dahl salt-sensitive (SS) rats, but far less is known about this relationship in females. Rats with genetically deleted T cells via CD247 gene mutation on the Dahl SS background (SSCD247-/-) were utilized to interrogate the effect of sex and T cells on salt sensitivity. METHODS: We assessed the hypertensive and kidney injury phenotypes in male versus female SS and SSCD247-/- rats challenged with 3 weeks of high salt (4.0% NaCl). Differences in T cell activation genes were examined in renal T cells from male and female SS rats, and a sex-specific adoptive transfer was performed by injecting male or female splenocytes into either male or female SSCD247-/- recipients to determine the potential contribution of T cell sex. RESULTS: The lack of functional T cells in SSCD247-/- rats significantly reduced salt-induced hypertension and proteinuria in both sexes, although SSCD247-/- females exhibited greater protection from kidney damage. Adoptive transfer of either Dahl SS male or female splenocytes into SSCD247-/- male recipients exacerbated hypertension and proteinuria compared with controls, while in SSCD247-/- female recipients, exacerbation of disease occurred only upon transfer of male, but not female, SS splenocytes. CONCLUSIONS: The absence of T cells in the SSCD247-/- normalized sex differences in blood pressure, though sex differences in renal damage persisted. Splenocyte transfer experiments demonstrated that salt sensitivity is amplified if the sex of the T cell or the recipient is male.


Subject(s)
Hypertension , Rats, Inbred Dahl , T-Lymphocytes , Animals , Male , Female , Rats , Hypertension/physiopathology , Hypertension/genetics , T-Lymphocytes/immunology , Sex Factors , Disease Models, Animal , Sodium Chloride, Dietary/adverse effects , Blood Pressure/physiology , Adoptive Transfer , Kidney/pathology , Kidney/metabolism
7.
Biochem Biophys Res Commun ; 722: 150147, 2024 Aug 30.
Article in English | MEDLINE | ID: mdl-38788356

ABSTRACT

We used an animal model of salt-sensitive hypertension (SSH) in which ovariectomized (oVx) rats developed hypertension with high salt (HS) intake. Hypertension is accompanied by changes in the percentage of CD4+ T lymphocytes, immune CD45+ cell infiltration into renal tissue, and changes in Na+, K+- ATPase (NKA) expression in both renal tissue and peripheral blood mononuclear cells (PBMCs). To determine whether the observed changes resulted from HS intake, high blood pressure, or both, hydralazine (HDZ) was used to lower blood pressure. The oVx HS rats received two HDZ schedules either to prevent or to treat hypertension. NKA was overexpressed in the kidneys of all oVx groups and in PBMCs of oVx HS rats. This pattern was not altered with HDZ treatment. Changes in CD4+ T lymphocytes and renal infiltration of CD45+ cells were not reversed either. High salt, but not high blood pressure, induces immune cell activation and renal infiltration. Overexpressed NKA is the primary event, and HS is the perturbation to the system in this model of SSH, which resembles the postmenopausal state.


Subject(s)
Hypertension , Kidney , Ovariectomy , Rats, Wistar , Animals , Female , Rats , Kidney/pathology , Kidney/metabolism , Kidney/immunology , Hypertension/immunology , Hypertension/pathology , Hypertension/metabolism , Sodium-Potassium-Exchanging ATPase/metabolism , Sodium Chloride, Dietary/adverse effects , Blood Pressure/drug effects , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Hydralazine/pharmacology
8.
J Dev Orig Health Dis ; 15: e9, 2024 May 09.
Article in English | MEDLINE | ID: mdl-38721989

ABSTRACT

Sodium overload during childhood impairs baroreflex sensitivity and increases arterial blood pressure and heart rate in adulthood; these effects persist even after high-salt diet (HSD) withdrawal. However, the literature lacks details on the effects of HSD during postnatal phases on cardiac ischemia/reperfusion responses in adulthood. The current study aimed to elucidate the impact of HSD during infancy adolescence on isolated heart function and cardiac ischemia/reperfusion responses in adulthood. Male 21-day-old Wistar rats were treated for 60 days with hypertonic saline solution (NaCl; 0.3M; experimental group) or tap water (control group). Subsequently, both groups were maintained on a normal sodium diet for 30 days. Subsequently, the rats were euthanized, and their hearts were isolated and perfused according to the Langendorff technique. After 30 min of the basal period, the hearts were subjected to 20 min of anoxia, followed by 20 min of reperfusion. The basal contractile function was unaffected by HSD. However, HSD elevated the left ventricular end-diastolic pressure during reperfusion (23.1 ± 5.2 mmHg vs. 11.6 ± 1.4 mmHg; p < 0.05) and increased ectopic incidence period during reperfusion (208.8 ± 32.9s vs. 75.0 ± 7.8s; p < 0.05). In conclusion, sodium overload compromises cardiac function after reperfusion events, diminishes ventricular relaxation, and increases the severity of arrhythmias, suggesting a possible arrhythmogenic effect of HSD in the postnatal phases.


Subject(s)
Arrhythmias, Cardiac , Myocardial Reperfusion Injury , Rats, Wistar , Animals , Rats , Arrhythmias, Cardiac/etiology , Arrhythmias, Cardiac/physiopathology , Male , Myocardial Reperfusion Injury/etiology , Myocardial Reperfusion Injury/physiopathology , Diastole/physiology , Sodium Chloride, Dietary/adverse effects , Heart Rate/physiology
9.
Brain Behav ; 14(5): e3516, 2024 May.
Article in English | MEDLINE | ID: mdl-38702903

ABSTRACT

BACKGROUND: High salt intake has been proposed as a risk factor for dementia. However, causal relationship between salt intake and dementia remains uncertain. PURPOSE: The aim of this study was to employ a mendelian randomization (MR) design to investigate the causal impact of salt intake on the risk of dementia. METHODS: Genome-wide association study (GWAS) data of exposures and outcomes (any dementia, cognitive performance, different types of dementia, Alzheimer's disease [AD], and Parkinson's disease) were obtained from the IEU database. MR estimates were generated though inverse-variance weighted model. MR-Egger, weighted median, and MR-Pleiotropy Residual Sum and Outlier (MR-PRESSO) method also used in our study. Sensitivity analyses included Cochran's Q test, MR-Egger intercept, MR-PRESSO global test and outlier test, leave-one-out analysis, and funnel plot assessment. RESULTS: Our MR analysis provided evidence of a causal association between high salt added to food and dementia (odds ratio [OR] = 1.73, 95% confidence interval [CI]: 1.21-2.49, and p = .003), dementia in AD (OR = 2.10, 95% CI: 1.15-3.83, and p = .015), and undefined dementia (OR = 2.61, 95% CI: 1.26-5.39, and p = .009). Higher salt added was also associated with increased risk of AD (OR = 1.80, 95% CI: 1.12-2.87, and p = .014) and lower cognitive performance (ß = -.133, 95% CI: -.229 to -.038, and p = .006). CONCLUSION: This study provides evidence suggesting that high salt intake is causally associated with an increased risk of developing dementia, including AD and undefined dementia, highlighting the potential importance of reducing salt consumption as a preventive measure.


Subject(s)
Dementia , Genome-Wide Association Study , Mendelian Randomization Analysis , Sodium Chloride, Dietary , Humans , Dementia/epidemiology , Dementia/genetics , Dementia/etiology , Sodium Chloride, Dietary/adverse effects , Sodium Chloride, Dietary/administration & dosage , White People/genetics , Risk Factors , Alzheimer Disease/genetics , Alzheimer Disease/epidemiology
10.
Physiol Rep ; 12(10): e16046, 2024 May.
Article in English | MEDLINE | ID: mdl-38749925

ABSTRACT

We have previously reported that the subfornical organ (SFO) does not contribute to the chronic hypertensive response to DOCA-salt in rats, and yet the organum vasculosum of the lamina terminalis (OVLT) plays a significant role in the development of deoxycorticosterone acetate (DOCA)-salt hypertension. Since efferent fibers of the OVLT project to and through the median preoptic nucleus (MnPO), the present study was designed to test the hypothesis that the MnPO is necessary for DOCA-salt hypertension in the rat. Male Sprague-Dawley rats underwent SHAM (MnPOsham; n = 5) or electrolytic lesion of the MnPO (MnPOx; n = 7) followed by subsequent unilateral nephrectomy and telemetry instrumentation. After recovery and during the experimental protocol, rats consumed a 0.1% NaCl diet and 0.9% NaCl drinking solution. Mean arterial pressure (MAP) was recorded telemetrically 5 days before and 21 days after DOCA implantation (100 mg/rat; SQ). The chronic pressor response to DOCA was attenuated in MnPOx rats by Day 11 of treatment and continued such that MAP increased 25 ± 3 mmHg in MnPOsham rats by Day 21 of DOCA compared to 14 ± 3 mmHg in MnPOx rats. These results support the hypothesis that the MnPO is an important brain site of action and necessary for the full development of DOCA-salt hypertension in the rat.


Subject(s)
Desoxycorticosterone Acetate , Hypertension , Preoptic Area , Rats, Sprague-Dawley , Animals , Male , Preoptic Area/drug effects , Preoptic Area/metabolism , Hypertension/chemically induced , Hypertension/physiopathology , Hypertension/etiology , Rats , Sodium Chloride, Dietary/adverse effects , Blood Pressure/drug effects
11.
Circ Res ; 134(10): 1234-1239, 2024 May 10.
Article in English | MEDLINE | ID: mdl-38723029

ABSTRACT

The year 2024 marks the centennial of the initiation of the American Heart Association. Over the past 100 years, the American Heart Association has led groundbreaking discoveries in cardiovascular disease including salt sensitivity of blood pressure, which has been studied since the mid-1900s. Salt sensitivity of blood pressure is an important risk factor for cardiovascular events, but the phenotype remains unclear because of insufficient understanding of the underlying mechanisms and lack of feasible diagnostic tools. In honor of this centennial, we commemorate the initial discovery of salt sensitivity of blood pressure and chronicle the subsequent scientific discoveries and efforts to mitigate salt-induced cardiovascular disease with American Heart Association leading the way. We also highlight determinants of the pathophysiology of salt sensitivity of blood pressure in humans and recent developments in diagnostic methods and future prospects.


Subject(s)
Blood Pressure , Hypertension , Sodium Chloride, Dietary , Animals , Humans , American Heart Association/history , Blood Pressure/drug effects , Cardiovascular Diseases/physiopathology , Cardiovascular Diseases/etiology , Hypertension/etiology , Hypertension/history , Hypertension/physiopathology , Sodium Chloride, Dietary/adverse effects , Sodium Chloride, Dietary/history , United States/epidemiology , History, 20th Century , History, 21st Century
12.
Curr Opin Nephrol Hypertens ; 33(4): 441-446, 2024 07 01.
Article in English | MEDLINE | ID: mdl-38639736

ABSTRACT

PURPOSE OF REVIEW: Salt-sensitive (SS) hypertension and its associated kidney damage have been extensively studied, yet proper therapeutic strategies are lacking. The interest in altering the metabolome to affect renal and cardiovascular disease has been emerging. Here, we discuss the effect and potential mechanism behind the protective effect of lysine, an essential amino acid, on the progression of SS hypertension. RECENT FINDINGS: We have recently demonstrated that administering lysine in an SS rodent model can control the progression of hypertension. Both the animal and pilot human studies showed that lysine can efficiently inhibit tubular reabsorption of albumin and protect the kidneys from further damage. In addition, we conducted multilevel omics studies that showed increased lysine conjugation and excretion, leading to the depletion of harmful metabolites and an increase in useful ones. SUMMARY: Lysine's twofold action involves both mechanically flushing protein from proximal tubules to shield the kidneys and initiating metabolic adaptations in the kidneys. This results in a net positive impact on SS hypertension. While further research is necessary to apply the current findings in clinical settings, this study offers some evidence suggesting that lysine supplementation holds promise as a therapeutic approach for hypertensive kidney disease.


Subject(s)
Hypertension , Lysine , Sodium Chloride, Dietary , Lysine/metabolism , Humans , Animals , Hypertension/metabolism , Hypertension/physiopathology , Hypertension/drug therapy , Sodium Chloride, Dietary/adverse effects , Kidney/metabolism , Kidney/drug effects , Blood Pressure/drug effects
13.
Hypertension ; 81(6): 1345-1355, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38618734

ABSTRACT

BACKGROUND: Every year, thousands of patients with hypertension reduce salt consumption in an effort to control their blood pressure. However, hypertension has a self-sustaining character in a significant part of the population. We hypothesized that chronic hypertension leads to irreversible renal damage that remains after removing the trigger, causing an elevation of the initial blood pressure. METHODS: Dahl salt-sensitive rat model was used for chronic, continuous observation of blood pressure. Rats were fed a high salt diet to induce hypertension, and then the diet was switched back to normal sodium content. RESULTS: We found that developed hypertension was irreversible by salt cessation: after a short period of reduction, blood pressure grew even higher than in the high-salt phase. Notably, the self-sustaining phase of hypertension was sensitive to benzamil treatment due to sustaining epithelial sodium channel hyperactivity, as shown with patch-clamp analysis. Glomerular damage and proteinuria were also irreversible. In contrast, some mechanisms, contributing to the development of salt-sensitive hypertension, normalized after salt restriction. Thus, flow cytometry demonstrated that dietary salt reduction in hypertensive animals decreased the number of total CD45+, CD3+CD4+, and CD3+CD8+ cells in renal tissues. Also, we found tubular recovery and improvement of glomerular filtration rate in the postsalt period versus a high-salt diet. CONCLUSIONS: Based on earlier publications and current data, poor response to salt restriction is due to the differential contribution of the factors recognized in the developmental phase of hypertension. We suggest that proteinuria or electrolyte transport can be prioritized over therapeutic targets of inflammatory response.


Subject(s)
Blood Pressure , Disease Models, Animal , Hypertension , Rats, Inbred Dahl , Sodium Chloride, Dietary , Animals , Hypertension/physiopathology , Hypertension/etiology , Rats , Sodium Chloride, Dietary/adverse effects , Blood Pressure/physiology , Blood Pressure/drug effects , Male , Kidney/pathology , Kidney/drug effects , Kidney/metabolism , Epithelial Sodium Channels/metabolism , Diet, Sodium-Restricted
14.
Ann Intern Med ; 177(5): 643-655, 2024 May.
Article in English | MEDLINE | ID: mdl-38588546

ABSTRACT

BACKGROUND: Salt substitution is a simple yet increasingly promising strategy to improve cardiovascular outcomes. PURPOSE: To evaluate the long-term effects of salt substitution on cardiovascular outcomes. DATA SOURCES: PubMed, EMBASE, Cochrane CENTRAL, and CINAHL searched from inception to 23 August 2023. Trial registries, citation analysis, and hand-search were also done. STUDY SELECTION: Randomized controlled trials (RCTs) comparing provision of or advice to use a salt substitute with no intervention or use of regular salt among adults for 6 months or longer in total study duration. DATA EXTRACTION: Two authors independently screened articles, extracted data, and assessed risk of bias. Primary outcomes include mortality, major cardiovascular events (MACE), and adverse events at 6 months or greater. Secondary and post hoc outcomes include blood pressure, cause-specific mortality, and urinary excretion at 6 months or greater. Random-effects meta-analyses were done and certainty of effect estimates were assessed using GRADE (Grading of Recommendations Assessment, Development and Evaluation). DATA SYNTHESIS: Of the 16 included RCTs, 8 reported on primary outcomes. Most (n = 7 of 8) were done in China or Taiwan, 3 were done in residential facilities, and 7 included populations of older age (average 62 years) and/or with higher-than-average cardiovascular risk. In this population, salt substitute may reduce risk for all-cause mortality (6 RCTs; 27 710 participants; rate ratio [RR], 0.88 [95% CI, 0.82 to 0.93]; low certainty) and cardiovascular mortality (4 RCTs; 25 050 participants; RR, 0.83 [CI, 0.73 to 0.95]; low certainty). Salt substitute may result in a slight reduction in MACE (3 RCTs; 23 215 participants; RR, 0.85 [CI, 0.71 to 1.00]; very low certainty), with very low-certainty evidence of serious adverse events (6 RCTs; 27 995 participants; risk ratio, 1.04 [CI, 0.87 to 1.25]). LIMITATIONS: The evidence base is dominated by a single, large RCT. Most RCTs were from China or Taiwan and involved participants with higher-than-average cardiovascular risk; therefore, generalizability to other populations is very limited. CONCLUSION: Salt substitution may reduce all-cause or cardiovascular mortality, but the evidence for reducing cardiovascular events and for not increasing serious adverse events is uncertain, particularly for a Western population. The certainty of evidence is higher among populations at higher cardiovascular risk and/or following a Chinese diet. PRIMARY FUNDING SOURCE: National Health and Medical Research Council. (PROSPERO: CRD42022327566).


Subject(s)
Cardiovascular Diseases , Humans , Cardiovascular Diseases/prevention & control , Cardiovascular Diseases/mortality , Diet, Sodium-Restricted , Sodium Chloride, Dietary/administration & dosage , Sodium Chloride, Dietary/adverse effects , Blood Pressure/drug effects , Randomized Controlled Trials as Topic , Hypertension
15.
Int J Mol Sci ; 25(8)2024 Apr 16.
Article in English | MEDLINE | ID: mdl-38673987

ABSTRACT

Sodium chloride (NaCl) activates Th17 and dendritic cells in hypertension by stimulating serum/glucocorticoid kinase 1 (SGK1), a sodium sensor. Memory T cells also play a role in hypertension by infiltrating target organs and releasing proinflammatory cytokines. We tested the hypothesis that the role of T cell SGK1 extends to memory T cells. We employed mice with a T cell deletion of SGK1, SGK1fl/fl × tgCD4cre mice, and used SGK1fl/fl mice as controls. We treated the mice with L-NAME (0.5 mg/mL) for 2 weeks and allowed a 2-week washout interval, followed by a 3-week high-salt (HS) diet (4% NaCl). L-NAME/HS significantly increased blood pressure and memory T cell accumulation in the kidneys and bone marrow of SGK1fl/fl mice compared to knockout mice on L-NAME/HS or groups on a normal diet (ND). SGK1fl/fl mice exhibited increased albuminuria, renal fibrosis, and interferon-γ levels after L-NAME/HS treatment. Myography demonstrated endothelial dysfunction in the mesenteric arterioles of SGK1fl/fl mice. Bone marrow memory T cells were adoptively transferred from either mouse strain after L-NAME/HS administration to recipient CD45.1 mice fed the HS diet for 3 weeks. Only the mice that received cells from SGK1fl/fl donors exhibited increased blood pressure and renal memory T cell infiltration. Our data suggest a new therapeutic target for decreasing hypertension-specific memory T cells and protecting against hypertension.


Subject(s)
Hypertension , Immediate-Early Proteins , NG-Nitroarginine Methyl Ester , Protein Serine-Threonine Kinases , Sodium Chloride, Dietary , Animals , Male , Mice , Blood Pressure/drug effects , Hypertension/chemically induced , Hypertension/metabolism , Hypertension/pathology , Immediate-Early Proteins/metabolism , Immediate-Early Proteins/genetics , Kidney/metabolism , Kidney/pathology , Mice, Inbred C57BL , Mice, Knockout , NG-Nitroarginine Methyl Ester/pharmacology , Protein Serine-Threonine Kinases/metabolism , Protein Serine-Threonine Kinases/genetics , Sodium Chloride, Dietary/adverse effects , T-Lymphocytes/metabolism , T-Lymphocytes/immunology
16.
Curr Hypertens Rep ; 26(6): 273-290, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38602583

ABSTRACT

PURPOSE OF REVIEW: Hypertension is a principal risk factor for cardiovascular morbidity and mortality, with its severity exacerbated by high sodium intake, particularly in individuals with salt-sensitive blood pressure. However, the mechanisms underlying hypertension and salt sensitivity are only partly understood. Herein, we review potential interactions in hypertension pathophysiology involving the immune system, endoplasmic reticulum (ER) stress, the unfolded protein response (UPR), and proteostasis pathways; identify knowledge gaps; and discuss future directions. RECENT FINDINGS: Recent advancements by our research group and others reveal interactions within and between adaptive and innate immune responses in hypertension pathophysiology. The salt-immune-hypertension axis is further supported by the discovery of the role of dendritic cells in hypertension, marked by isolevuglandin (IsoLG) formation. Alongside these broadened understandings of immune-mediated salt sensitivity, the contributions of T cells to hypertension have been recently challenged by groups whose findings did not support increased resistance of Rag-1-deficient mice to Ang II infusion. Hypertension has also been linked to ER stress and the UPR. Notably, a holistic approach is needed because the UPR engages in crosstalk with autophagy, the ubiquitin proteasome, and other proteostasis pathways, that may all involve hypertension. There is a critical need for studies to establish cause and effect relationships between ER stress and the UPR in hypertension pathophysiology in humans and to determine whether the immune system and ER stress function mainly to exacerbate or initiate hypertension and target organ injury. This review of recent studies proposes new avenues for future research for targeted therapeutic interventions.


Subject(s)
Blood Pressure , Endoplasmic Reticulum Stress , Hypertension , Unfolded Protein Response , Hypertension/physiopathology , Endoplasmic Reticulum Stress/drug effects , Humans , Animals , Blood Pressure/physiology , Sodium Chloride, Dietary/adverse effects , Proteostasis
17.
J Clin Hypertens (Greenwich) ; 26(6): 735-739, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38685612

ABSTRACT

We conducted a pre-post intervention study to determine knowledge, attitude, and practice toward dietary salt intake before, immediately, and 1-month after nurse-led one-on-one counseling. We purposively selected three public health facilities in Agra, India, and enrolled all eligible hypertensive patients aged 18-60 under treatment for ≥6 months. Of the 153 patients at the 1-month follow-up, counseling improved knowledge (4% vs. 42%, p < .001), a greater prioritization of a low salt diet (34% vs. 52%, p < .001), and practice of adding less salt to the dough (48% to 41%, p < .001). The counseling intervention improved knowledge, attitude, and practice toward dietary salt intake.


Subject(s)
Health Knowledge, Attitudes, Practice , Hypertension , Sodium Chloride, Dietary , Humans , India/epidemiology , Hypertension/diet therapy , Hypertension/epidemiology , Female , Male , Adult , Middle Aged , Sodium Chloride, Dietary/administration & dosage , Sodium Chloride, Dietary/adverse effects , Diet, Sodium-Restricted/methods , Public Sector , Counseling/methods , Patient Education as Topic/methods , Young Adult
18.
Metab Syndr Relat Disord ; 22(5): 356-364, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38563778

ABSTRACT

Background and Objective: Hypertension and type-2 diabetes are strong risk factors for cardiovascular diseases, and their management requires lifestyle changes, including a shift in dietary habits. The consumption of salt has increased in the last decades in some countries, but its association with type-2 diabetes remains unknown. Thus, we aimed to estimate the amount of salt intake among adults with and without diabetes and to assess whether concomitant hypertension and diabetes are associated with higher salt intake. Methods: Data from 11,982 adults 35-74 years of age enrolled in the baseline of the Longitudinal Study of Adult Health-Brasil study (2008-2010) were studied. A clinical and anthropometric evaluation was performed, and their daily salt intake was estimated by the overnight 12-hr urine sodium excretion. Results: Salt intake (gram per day) was higher in participants with diabetes as compared with those without diabetes, regardless of sex (men: 14.2 ± 6.4 vs. 12.4 ± 5.6, P < 0.05; women: 10.5 ± 4.8 vs. 9.1 ± 4.1, P < 0.05). However, salt intake is high in participants with fasting glucose ≥126 mg/dL or HbA1c ≥6.5%, but not in participants with blood glucose 2 hr after the glucose tolerance test ≥200 mg/dL. When hypertension and diabetes coexisted, salt consumption was higher than among people without these conditions. The prevalence of hypertension increased with increasing salt intake in women with diabetes, but not in men with this condition. Conclusions: Our findings highlight the high consumption of salt in individuals with diabetes and/or hypertension, and the need for effective strategies to reduce salt consumption in these groups of increased risk for major cardiovascular events, especially in women.


Subject(s)
Diabetes Mellitus, Type 2 , Hypertension , Sodium Chloride, Dietary , Humans , Female , Middle Aged , Male , Longitudinal Studies , Adult , Hypertension/epidemiology , Hypertension/complications , Sodium Chloride, Dietary/adverse effects , Sodium Chloride, Dietary/administration & dosage , Brazil/epidemiology , Aged , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/complications , Risk Factors , Blood Pressure , Blood Glucose/metabolism , Blood Glucose/analysis
19.
Sci Rep ; 14(1): 7970, 2024 04 04.
Article in English | MEDLINE | ID: mdl-38575652

ABSTRACT

Dietary salt has been associated with cognitive impairment in mice, possibly related to damaged synapses and tau hyperphosphorylation. However, the mechanism underlying how dietary salt causes cognitive dysfunction remains unclear. In our study, either a high-salt (8%) or normal diet (0.5%) was used to feed C57BL/6 mice for three months, and N2a cells were cultured in normal medium, NaCl medium (80 mM), or NaCl (80 mM) + Liraglutide (200 nM) medium for 48 h. Cognitive function in mice was assessed using the Morris water maze and shuttle box test, while anxiety was evaluated by the open field test (OPT). Western blotting (WB), immunofluorescence, and immunohistochemistry were utilized to assess the level of Glucagon-like Peptide-1 receptor (GLP-1R) and mTOR/p70S6K pathway. Electron microscope and western blotting were used to evaluate synapse function and tau phosphorylation. Our findings revealed that a high salt diet (HSD) reduced the level of synaptophysin (SYP) and postsynaptic density 95 (PSD95), resulting in significant synaptic damage. Additionally, hyperphosphorylation of tau at different sites was detected. The C57BL/6 mice showed significant impairment in learning and memory function compared to the control group, but HSD did not cause anxiety in the mice. In addition, the level of GLP-1R and autophagy flux decreased in the HSD group, while the level of mTOR/p70S6K was upregulated. Furthermore, liraglutide reversed the autophagy inhibition of N2a treated with NaCl. In summary, our study demonstrates that dietary salt inhibits the GLP-1R/mTOR/p70S6K pathway to inhibit autophagy and induces synaptic dysfunction and tau hyperphosphorylation, eventually impairing cognitive dysfunction.


Subject(s)
Cognitive Dysfunction , Liraglutide , Mice , Animals , Liraglutide/pharmacology , Sodium Chloride, Dietary/adverse effects , Glucagon-Like Peptide-1 Receptor/metabolism , Sodium Chloride/pharmacology , Ribosomal Protein S6 Kinases, 70-kDa/metabolism , Mice, Inbred C57BL , Signal Transduction , Cognitive Dysfunction/etiology , Cognitive Dysfunction/metabolism , TOR Serine-Threonine Kinases/metabolism , Cognition
20.
J Clin Hypertens (Greenwich) ; 26(5): 543-552, 2024 May.
Article in English | MEDLINE | ID: mdl-38563696

ABSTRACT

The Australian culturally and linguistically diverse (CALD) communities may be at higher risk of salt intake than recommended given the use of a combination of discretionary sources and exposure to processed foods within a western country. This survey aimed to understand the knowledge, attitudes, and behaviors toward dietary salt and the acceptability of salt substitutes in the CALD communities. An online cross-sectional survey was conducted among adults who self-reported being a part of a CALD community, which was defined as non-Indigenous cultural groups in Australia having cultural or linguistic connections with their overseas place of birth, ancestry or ethnic origin, religion, preferred language or language spoken at home. A total of 218 respondents opened the survey link. A total of 196 completed the entire survey. The majority of respondents (162, 83%) were aware that high salt intake causes serious health problems. Altogether 134 (69%) respondents were aware that there is a recommended amount for daily salt consumption although only 59 (44%) knew precise recommendations as <5 g salt per day. Around one quarter of the respondents rarely or never looked for ?low in salt'' or ?reduced salt'' messages on food labels when shopping. Over half specified they always or often added salt during cooking or preparing foods in the household. Almost 4 in 5 CALD respondents were willing to reduce their salt intake for health and 3 in 4 were open to trying a salt substitute. Further research into the utility of a salt substitute intervention in the Australian CALD community is warranted.


Subject(s)
Health Knowledge, Attitudes, Practice , Sodium Chloride, Dietary , Humans , Australia/epidemiology , Cross-Sectional Studies , Female , Male , Adult , Sodium Chloride, Dietary/administration & dosage , Sodium Chloride, Dietary/adverse effects , Middle Aged , Surveys and Questionnaires , Hypertension/ethnology , Hypertension/epidemiology , Aged , Cultural Diversity , Language , Young Adult
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