Salt Sensitivity Of Blood Pressure Research Articles

Salt Sensitivity of Blood Pressure in Blacks and Women: A Role of Inflammation, Oxidative Stress, and Epithelial Na+ Channel.

Significance: Salt sensitivity of blood pressure (SSBP) is an independent risk factor for mortality and morbidity due to cardiovascular disease, and disproportionately affects blacks and women. Several mechanisms have been proposed, including exaggerated activation of sodium transporters in the kidney leading to salt retention and water. Recent Advances: Recent studies have found that in addition to the renal epithelium, myeloid immune cells can sense sodium via the epithelial Na+ channel (ENaC), which leads to activation of the nicotinamide adenine dinucleotide phosphate oxidase enzyme complex, increased fatty acid oxidation, and production of isolevuglandins (IsoLGs). IsoLGs are immunogenic and contribute to salt-induced hypertension. In addition, aldosterone-mediated activation of ENaC has been attributed to the increased SSBP in women. The goal of this review is to highlight mechanisms contributing to SSBP in blacks and women, including, but not limited to increased activation of ENaC, fatty acid oxidation, and inflammation. Critical Issues: A critical barrier to progress in management of SSBP is that its diagnosis is not feasible in the clinic and is limited to expensive and laborious research protocols, which makes it difficult to investigate. Yet without understanding the underlying mechanisms, this important risk factor remains without treatment. Future Directions: Further studies are needed to understand the mechanisms that contribute to differential blood pressure responses to dietary salt and find feasible diagnostic tools. This is extremely important and may go a long way in mitigating the racial and sex disparities in cardiovascular outcomes. Antioxid. Redox Signal. 35, 1477-1493.

Salt-Sensitivity of Blood Pressure and Insulin Resistance.

Salt sensitivity of blood pressure (SSBP) is an independent risk factor for cardiovascular morbidity and mortality that is seen in both hypertensive and normotensive populations. Insulin resistance (IR) strongly correlates with SSBP and affects nearly 50% of salt sensitive people. While the precise mechanism by which IR and SSBP relate remains elusive, several common pathways are involved in the genesis of both processes, including vascular dysfunction and immune activation. Vascular dysfunction associated with insulin resistance is characterized by loss of nitric oxide (NO)-mediated vasodilation and heightened endothelin-1 induced vasoconstriction, as well as capillary rarefaction. It manifests with increased blood pressure (BP) in salt sensitive murine models. Another common denominator in the pathogenesis of insulin resistance, hypertension, and salt sensitivity (SS) is immune activation involving pro-inflammatory cytokines like tumor necrosis factor (TNF)-α, IL-1β, and IL-6. In the last decade, a new understanding of interstitial sodium storage in tissues such as skin and muscle has revolutionized traditional concepts of body sodium handling and pathogenesis of SS. We have shown that interstitial Na+ can trigger a T cell mediated inflammatory response through formation of isolevuglandin protein adducts in antigen presenting cells (APCs), and that this response is implicated in salt sensitive hypertension. The peroxisome proliferator-activated receptor γ (PPARγ) is a transcription factor that modulates both insulin sensitivity and BP. PPARγ agonists increase insulin sensitivity and ameliorate salt sensitivity, whereas deficiency of PPARγ results in severe insulin resistance and hypertension. These findings suggest that PPARγ plays a role in the common pathogenesis of insulin sensitivity and salt sensitivity, perhaps via effects on the immune system and vascular function. The goal of this review is to discuss those mechanisms that may play a role in both SSBP and in insulin resistance.

Association of Circulating Biomarkers of lnc-IGSF3-1:1, SCOC-AS1, and SLC8A1-AS1 with Salt Sensitivity of Blood Pressure in Chinese Population.

Accumulating evidence suggested that long non-coding RNAs (lncRNAs) could play biological roles in cardiovascular diseases. We investigated whether lncRNAs can serve as biomarkers for salt sensitivity of blood pressure (SSBP). Participants were divided into salt-sensitive (SS) and salt-resistant (SR) ones by oral saline test. LncRNAs were tested by microarray (N = 20) and two-stage qRT-PCR (N = 89 and 228). We identified five differently expressed lncRNAs (lnc-IGSF3-1:1, SCOC-AS1, SLC8A1-AS1, KCNQ1OT1, and lnc-GNG-10-3:1) between SS and SR. In single-lncRNA analyses, lnc-IGSF3-1:1 displayed better diagnostic performance in hypertensive patients (AUC = 0.840), while SCOC-AS1 in normotensive (AUC = 0.810). In multi-lncRNA analyses, lnc-IGSF3-1:1 + SCOC-AS1 + SLC8A1-AS1 combination showed the best diagnostic performance in hypertensive (AUC = 0.853) and normotensive groups (AUC = 0.873). We constructed a lncRNA-mRNA-GO-KEGG-disease network by bioinformatic analysis; lnc-IGSF3-1:1 and SLC8A1-AS1 were identified as hub biomarkers. Our findings suggest that lnc-IGSF3-1:1, SCOC-AS1, and SLC8A1-AS1 may represent as genetic susceptible biomarkers for SSBP, and had different SS diagnostic performance in hypertensive patients and normotensive individuals.

Genetic Predictors of Salt Sensitivity of Blood Pressure: The Additive Impact of 2 Hits in the Same Biological Pathway.

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Sensory Afferent Renal Nerve Activated Gαi2 Subunit Proteins Mediate the Natriuretic, Sympathoinhibitory and Normotensive Responses to Peripheral Sodium Challenges.

We have previously reported that brain Gαi2 subunit proteins are required to maintain sodium homeostasis and are endogenously upregulated in the hypothalamic paraventricular nucleus (PVN) in response to increased dietary salt intake to maintain a salt resistant phenotype in rats. However, the origin of the signal that drives the endogenous activation and up-regulation of PVN Gαi2 subunit protein signal transduction pathways is unknown. By central oligodeoxynucleotide (ODN) administration we show that the pressor responses to central acute administration and central infusion of sodium chloride occur independently of brain Gαi2 protein pathways. In response to an acute volume expansion, we demonstrate, via the use of selective afferent renal denervation (ADNX) and anteroventral third ventricle (AV3V) lesions, that the sensory afferent renal nerves, but not the sodium sensitive AV3V region, are mechanistically involved in Gαi2 protein mediated natriuresis to an acute volume expansion [peak natriuresis (μeq/min) sham AV3V: 43 ± 4 vs. AV3V 45 ± 4 vs. AV3V + Gαi2 ODN 25 ± 4, p < 0.05; sham ADNX: 43 ± 4 vs. ADNX 23 ± 6, AV3V + Gαi2 ODN 25 ± 3, p < 0.05]. Furthermore, in response to chronically elevated dietary sodium intake, endogenous up-regulation of PVN specific Gαi2 proteins does not involve the AV3V region and is mediated by the sensory afferent renal nerves to counter the development of the salt sensitivity of blood pressure (MAP [mmHg] 4% NaCl; Sham ADNX 124 ± 4 vs. ADNX 145 ± 4, p < 0.05; Sham AV3V 125 ± 4 vs. AV3V 121 ± 5). Additionally, the development of the salt sensitivity of blood pressure following central ODN-mediated Gαi2 protein down-regulation occurs independently of the actions of the brain angiotensin II type 1 receptor. Collectively, our data suggest that in response to alterations in whole body sodium the peripheral sensory afferent renal nerves, but not the central AV3V sodium sensitive region, evoke the up-regulation and activation of PVN Gαi2 protein gated pathways to maintain a salt resistant phenotype. As such, both the sensory afferent renal nerves and PVN Gαi2 protein gated pathways, represent potential targets for the treatment of the salt sensitivity of blood pressure.

Abstract 14155: Exposure to sFlt1-Induced Preeclampsia Enhances the Future Vascular Response to Hypertensive Stimuli in Mice in a Smooth Muscle Mineralocorticoid Receptor Dependent Manner

Preeclampsia (PE), a syndrome of high blood pressure (BP) and renal damage in late pregnancy, is associated with increased soluble VEGF receptor (sFlt1) and survivors have increased risk of future hypertension with increased angiotensin II (AngII) and salt sensitivity. Since smooth muscle cell mineralocorticoid receptor (SMC-MR) can be activated by hypertensive stimuli, we hypothesized that high sFlt1 exposure during pregnancy may induce a post-partum state of enhanced vascular sensitivity via SMC-MR activation. A PE model was induced by transient viral expression of sFlt1 in pregnant C57Bl6 mice. Elevated serum sFlt1, BP and glomerular endotheliosis was confirmed which all resolve post-partum. Two months later, resistance arteries from post-PE mice show no change in vasoconstriction to AngII but with increased mRNA ratio of the pro-constrictive AngII receptor-1(ATR1) to the vasodilatory ATR2. In a small cohort of women with prior PE, we confirm salt sensitivity of BP thus, postpartum mice were implanted with telemetric BP monitors and exposed to high salt or AngII (600mg/kg/day) infusion. Mice with prior PE had a significantly increased BP response to hypertensive stimuli. Microvessels from mice after PE and hypertensive stimuli had enhanced ex vivo myogenic tone and AngII vasoconstriction. To test the direct impact of sFlt1 on SMC-MR function, cultured SMC (Pac1) were transiently exposed to sFlt1 (24 hours on then off) to mimic the post-PE state. SMC-MR transcriptional activity in response to aldosterone and AngII were significantly increased after sFlt1 exposure as measured by luciferase reporter assay. SMC-MR activation and target gene expression was also enhanced after sFlt1 exposure (including AT1R/AT2R ratio). Finally, the role of SMC-MR in the post-PE phenotype was tested in vivo by PE induction in SMC-MR-KO vs MR-intact littermates. Post partum, SMC-MR-KO mice were protected from the PE-induced increase in aortic stiffness, microvascular myogenic tone and AngII vasoconstriction. sFlt1-induced PE produces a state of enhanced sensitivity to AngII that may be mediated by increased activation of SMC-MR. These data support the use of MR antagonists to mitigate the increased risk of cardiovascular disease in women exposed to PE.

Enhanced Thrombotic Responses Are Associated With Striatin Deficiency and Aldosterone.

BackgroundIn addition to its role on blood pressure, aldosterone (ALDO) also affects the hemostatic system leading to increased experimental thrombosis. Striatin is an intermediate in the rapid, nongenomic actions of ALDO. Striatin heterozygote knockout (Strn +/‐ ) mice have salt sensitivity of blood pressure and mildly chronically increased ALDO levels. In addition, in humans, striatin polymorphic gene variants are associated with increased salt sensitivity of blood pressure. Thus, we hypothesized that striatin deficiency would be associated with an increased prothrombotic response.Methods and Results Strn+/ ‐ mice and wild‐type littermates were maintained on a liberal sodium diet (1.6%). We measured in vivo thrombus formation following laser‐induced injury in cremaster arterioles using intravital microscopy. Mice were randomized to intravenous administration of ALDO or its vehicle. Acutely, ALDO increased thrombotic responses in wild‐type mice (P<0.01) versus controls within minutes as determined by increased platelet accumulation and fibrin deposition at the site of laser injury. We then compared thrombus formation without ALDO administration in Strn+/‐ and wild‐type mice. Strn+/‐ mice showed highly significant increases in laser‐induced thrombosis (P<0.001), as shown by increased platelet accumulation and fibrin deposition. Interestingly, the response in the Strn+/‐ mice basally was far greater than the wild‐type mice with ALDO administration, and ALDO administration produced no additional effect on thrombus responses in Strn+/‐ mice.ConclusionsThese results demonstrate a novel protective role of striatin in experimental thrombosis. Such a protective effect may be reduced in human striatin risk allele carriers, given the similar salt sensitivity of blood pressure in these individuals and Strn+/‐ mice.

Salt-Sensitive Hypertension, Renal Injury, and Renal Vasodysfunction Associated With Dahl Salt-Sensitive Rats Are Abolished in Consomic SS.BN1 Rats.

BackgroundAbnormal renal hemodynamic responses to salt‐loading are thought to contribute to salt‐sensitive (SS) hypertension. However, this is based largely on studies in anesthetized animals, and little data are available in conscious SS and salt‐resistant rats.Methods and ResultsWe assessed arterial blood pressure, renal function, and renal blood flow during administration of a 0.4% NaCl and a high‐salt (4.0% NaCl) diet in conscious, chronically instrumented 10‐ to 14‐week‐old Dahl SS and consomic SS rats in which chromosome 1 from the salt‐resistant Brown‐Norway strain was introgressed into the genome of the SS strain (SS.BN1). Three weeks of high salt intake significantly increased blood pressure (20%) and exacerbated renal injury in SS rats. In contrast, the increase in blood pressure (5%) was similarly attenuated in Brown‐Norway and SS.BN1 rats, and both strains were completely protected against renal injury. In SS.BN1 rats, 1 week of high salt intake was associated with a significant decrease in renal vascular resistance (−8%) and increase in renal blood flow (15%). In contrast, renal vascular resistance failed to decrease, and renal blood flow remained unchanged in SS rats during high salt intake. Finally, urinary sodium excretion and glomerular filtration rate were similar between SS and SS.BN1 rats during 0.4% NaCl and high salt intake.ConclusionsOur data support the concept that renal vasodysfunction contributes to blood pressure salt sensitivity in Dahl SS rats, and that genes on rat chromosome 1 play a major role in modulating renal hemodynamic responses to salt loading and salt‐induced hypertension.

Renocardiac protective effects of SGLT2 inhibitor combined with angiotensin receptor blocker in salt sensitive Dahl rats

Abstract Background Kidney plays a central role in regulating salt-sensitivity of blood pressure (BP) to governs sodium excretion via several mechanisms including pressure natriuresis and the actions of renal sodium transporters. Purpose We clarified the effects of combination treatment of sodium-glucose cotransporter 2 (SGLT2) inhibitor and angiotensin receptor blocker (ARB) on BP and the pathogenesis of renocardiac injuries, and elucidated underlying molecular mechanisms involved in the regulation of renal sodium handling in the development of salt-sensitivity by comparing with each monotreatment in Dahl salt-sensitive (DSS) hypertensive rats. Methods DSS rats were treated orally for 8-weeks with normal salt diet (0.3% NaCl) (NS/Cont group), high salt diet (8% NaCl) (HS/Cont group), high salt diet with ipragliflozin (0.04%) (HS/Ipra group), high salt diet with losartan (0.05%) (HS/Los group), or high salt diet with combination of ipragliflozin and losartan (HS/Ipra+Los group). Results The combination group significantly reduced systolic BP compared with either high salt diet control group, losartan or ipragliflozin monotreatment groups (HS/Ipra+Los: 182.5±18.4mmHg vs HS/Cont: 227.7±26.1; HS/Ipra: 216.6±26.9; HS/Los: 208.6±21.6, at 8-weeks of treatment, P&amp;lt;0.05, respectively) (Figure 1A). The slope of pressure-natriuresis curve was significantly increased in the HS/Ipra+Los group compared to that in the HS/Cont group (interaction P=0.024), HS/Ipra group (P=0.009), and HS/Los group (P=0.084) using the linear regression model (Figure 1B), which indicated that only the combination treatment of ipragliflozin and losartan improved salt-sensitivity. The combined treatment significantly improved creatinine clearance (HS/Ipra+Los: 3.3±0.9mL/min vs HS/Cont: 1.1±0.5; HS/Ipra: 1.7±0.6; HS/Los: 1.9±0.8, P&amp;lt;0.05, respectively). The combination treatment also significantly ameliorated glomerulosclerosis, and improved cardiomyocyte hypertrophy and perivascular fibrosis (Figure 1C). Angiotensin II type 1 receptor (AT1R) protein expression level in the kidney was remarkably suppressed in the combination treatment group compared to the other high salt diet groups. The protein expression level of Na+/H+ exchanger isoform 3 (NHE3) and Na+-K+-Cl– cotransporter 2 (NKCC2), two of major sodium transports in the renal tubules, were significantly decreased with losartan monotreatment and combination treatment, but not with ipragliflozin monotreatment (Figure 2). Conclusions The dual inhibition of SGLT2 and AT1R effectively improved salt-sensitivity via reducing renal expression levels of the sodium transporters, which eventually lead to renocardiac protection. Thus, the combination treatment could be a novel and useful therapeutic strategy for treating salt-sensitive hypertension and renal injury in non-diabetic patients. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Grant-in-Aid for Scientific Research

Salt sensitivity of volume and blood pressure in a mouse with globally reduced ENaC γ-subunit expression.

The epithelial Na+ channel (ENaC) promotes the absorption of Na+ in the aldosterone-sensitive distal nephron, colon, and respiratory epithelia. Deletion of genes encoding subunits of ENaC results in early postnatal mortality. Here, we present the initial characterization of a mouse with dramatically suppressed expression of the ENaC γ-subunit. We used this hypomorphic (γmt) allele to explore the importance of this subunit in homeostasis of electrolytes and body fluid volume. At baseline, γ-subunit expression in γmt/mt mice was markedly suppressed in the kidney and lung, whereas electrolytes resembled those of littermate controls. Aldosterone levels in γmt/mt mice exceeded those seen in littermate controls. Quantitative magnetic resonance measurement of body composition revealed similar baseline body water, lean tissue mass, and fat tissue mass in γmt/mt mice and controls. γmt/mt mice exhibited a more rapid decline in body water and lean tissue mass in response to a low-Na+ diet than the controls. Replacement of drinking water with 2% saline selectively and transiently increased body water and lean tissue mass in γmt/mt mice relative to the controls. Lower blood pressures were variably observed in γmt/mt mice on a high-salt diet compared with the controls. γmt/mt also exhibited reduced diurnal blood pressure variation, a "nondipping" phenotype, on a high-Na+ diet. Although ENaC in the renal tubules and colon works to prevent extracellular fluid volume depletion, our observations suggest that ENaC in other tissues may participate in regulating extracellular fluid volume and blood pressure.NEW & NOTEWORTHY A mouse with globally suppressed expression of the epithelial Na+ channel γ-subunit showed enhanced sensitivity to dietary salt, including a transient increase in total body fluid, reduced blood pressure, and reduced diurnal blood pressure variation when given a dietary NaCl challenge. These results point to a role for the epithelial Na+ channel in regulating body fluid and blood pressure beyond classical transepithelial Na+ transport mechanisms.

Candidate Gene Polymorphisms Influence the Susceptibility to Salt Sensitivity of Blood Pressure in a Han Chinese Population: Risk Factors as Mediators.

Genome-wide association studies suggest that there is a significant genetic susceptibility to salt sensitivity of blood pressure (SSBP), but it still needs to be verified in varied and large sample populations. We attempted to verify the associations between single-nucleotide polymorphisms (SNPs) in candidate genes and SSBP and to estimate their interaction with potential risk factors. A total of 29 candidate SNPs were genotyped in the 2,057 northern Han Chinese population from the Systems Epidemiology Study on Salt Sensitivity. A modified Sullivan’s acute oral saline load and diuresis shrinkage test (MSAOSL-DST) was used to identify SSBP. A generalized linear model was conducted to analyze the association between SNPs and SSBP, and Bonferroni correction was used for multiple testing. Mediation analysis was utilized to explore the mediation effect of risk factors. Eleven SNPs in eight genes (PRKG1, CYBA, BCAT1, SLC8A1, AGTR1, SELE, CYP4A11, and VSNL1) were identified to be significantly associated with one or more SSBP phenotypes (P < 0.05). Four SNPs (PRKG1/rs1904694 and rs7897633, CYP4A11/rs1126742, and CYBA/rs4673) were still significantly associated after Bonferroni correction (P < 0.0007) adjusted for age, sex, fasting blood glucose, total cholesterol, salt-eating habit, physical activity, and hypertension. Stratified analysis showed that CYBA/rs4673 was significantly associated with SSBP in hypertensive subjects (P < 0.0015) and CYP4A11/rs1126742 was significantly associated with SSBP in normotensive subjects (P < 0.0015). Subjects carrying both CYBA/rs4673-AA and AGTR1/rs2638360-GG alleles have a higher genetic predisposition to salt sensitivity due to the potential gene co-expression interaction. Expression quantitative trait loci analysis (eQTL) suggested that the above positive four SNPs showed cis-eQTL effects on the gene expression levels. Mediation analysis suggested that several risk factors were mediators of the relation between SNP and SSBP. This study suggests that the genetic variants in eight genes might contribute to the susceptibility to SSBP, and other risk factors may be the mediators.

Capnometric feedback training decreases 24-h blood pressure in hypertensive postmenopausal women

BackgroundHigh normal resting pCO2 is a risk factor for salt sensitivity of blood pressure (BP) in normotensive humans and has been associated with higher resting systolic BP in postmenopausal women. To date, however, no known studies have investigated the effects of regular practice of voluntary mild hypocapnic breathing on BP in hypertensive patients. The objective of the present research was to test the hypothesis that capnometric feedback training can decrease both resting pCO2 and 24-h BP in a series of mildly hypertensive postmenopausal women.MethodsA small portable end tidal CO2 (etCO2) monitor was constructed and equipped with software that determined the difference between the momentary etCO2 and a pre-programmed criterion range. The monitor enabled auditory feedback for variations in CO2 outside the criterion range. 16 mildly hypertensive postmenopausal women were individually trained to sustain small decreases in etCO2 during six weekly sessions in the clinic and daily sessions at home. 24-h BP monitoring was conducted before and after the intervention, and in 16 prehypertensive postmenopausal women in a control group who did not engage in the capnometric training.ResultsFollowing the intervention, all 16 capnometric training participants showed decreases in resting etCO2 (− 4.3 ± 0.4 mmHg; p < .01) while 15 showed decreases in 24-h systolic BP (− 7.6 ± 2.0 mmHg; p < .01). No significant changes in either measure was observed in the control group. In addition, nighttime (− 9.5 ± 2.6; p < .01) and daytime (− 6.7 ± 0.2 mmHg) systolic BP were both decreased following capnometric training, while no significant changes in nighttime (− 2.8 ± 2.2 mmHg; p = .11) or daytime (− 0.7 ± 1.0 mmHg; p ≤ .247) systolic BP were observed in the control group.ConclusionsThese findings support the hypothesis that regular practice of mild hypocapnic breathing that decreases resting etCO2 reliably decreases 24-h blood pressure in hypertensive postmenopausal women. The extent to which these effects persist beyond the training period or can be observed in other hypertensive subgroups remains to be investigated.

Abstract 11: Single Cell Eccite-seq Analysis Reveal An Important Role Of Monocyte-specific Nlrp3 Inflammasome For Salt-sensitivity Of Hypertension In Humans

Salt sensitivity of blood pressure is an independent predictor of death due to cardiovascular events. Diagnosis of salt-sensitivity is not feasible in the clinic, making it difficult to investigate therapeutic strategies. We hypothesized that NLRP3-inflammasome and IL-1β production in monocytes plays a role in salt-sensitive hypertension. We phenotyped salt-sensitivity of blood pressure using an acute inpatient Weinberger protocol of an isocaloric high salt diet and rapid intravenous salt-loading, followed by low salt diet and furosemide-induced salt-depletion. Ambulatory blood pressure was continuously monitored and averaged for the days of salt-loading and salt-depletion. Blood samples were obtained at baseline, salt-loading, and after salt-depletion. Median age was 54 years (44-55), 3 of the 5 subjects were female, screening systolic blood pressure was 140 mmHg (134-148), diastolic blood pressure was 88 mmHg (84-99), and BMI was 35 kg/m 2 (30-39). Using cell hashing and ECCITE-seq analysis, we profiled transcriptomes in multiple immune cell types using antibody-derived tags (ADTs). UMAP clustering of different cell types were identified by ADTs including monocyte markers CD14 and CD16. Interestingly, UMAP visualization of CD14+ and CD16+ clusters indicated a greater decrease in CD14+ clusters after salt-depletion in the salt-resistant subjects than the salt-sensitive; however the salt-sensitive subjects had a greater decrease in CD16+ clusters than the salt-resistant group after both salt-loading and salt-depletion. These data were confirmed using flow cytometry. Unlike in salt-resistant participants, we found that within monocyte clusters, salt-sensitivity was associated with down regulation of the inflammasome components NLRP3 (0.386 ± 1.18 vs. 0.197 ± 0.778) and IL-1β (0.858 ± 2.32 vs. 0.159 ± 0.925) following salt-depletion. Using flow cytometry, we found Δ% isoLG+ CD14+/CD16+ monocytes correlated with salt-sensitivity of blood pressure (r=0.88, 95% CI, p=0.05). These results suggest that the inflammasome and monocyte activation are dynamically regulated by dietary salt in vivo and can serve as a potential diagnostic biomarker for salt-sensitivity of blood pressure.

Abstract MP32: Renal Tubular Epithelial Cell-derived IL-1β Triggers The Inflammatory Response That Induces Salt Sensitivity In Diabetes

Renal inflammation, and specifically interleukin (IL)-6, induces salt-sensitivity in diabetic mice by upregulating the epithelial sodium channel (ENaC). However, the origin of this inflammatory response is still unknown. We hypothesize that, during diabetes, tubular epithelial cells initiate renal inflammation by releasing IL-1β that further activates renal macrophages to produce IL-6 and impair kidney function. A primary culture of renal tubular epithelial cells from wild-type (WT) mice was exposed to either low (LG, 5mM) or high (HG, 15mM) glucose media. HG-treated cells released higher levels of IL-1β (28 ± 12 vs. 8 ± 4 pg/ml, P&lt;0.01) and have higher expression of NLRP3 (4 ± 1 fold increase, P&lt;0.001) and Caspase-1 (2.1 ± 0.2 fold increase, P&lt;0.001) compared to LG-treated cells. No effect was observed using mannitol as an osmotic control. Tubular cells were also co-cultured with bone marrow-derived macrophages. Flow cytometry analysis revealed that HG-treated tubular cells induced an M1-type polarization of macrophages. This effect was blunted when macrophages were obtained from IL-1 receptor KO mice (IL1RKO) confirming a role of IL-1β. Here, the percentage of M1 macrophages (CD45 + F4/80 + CD80 + ) of total macrophages (CD45 + F4/80 + ) decreased from 31 ± 4% to 10 ± 3% (P&lt;0.01). To evaluate whether IL-1β-mediated macrophage activation plays a role in vivo, 2-mo-old diabetic db/db mice (n=6) were transplanted with bone marrow from IL1RKO mice. In these mice, named db/db-IL1RKO, immune cells cannot respond to IL-1β. Db/db receiving wild-type (WT) bone marrow (db/db-WT) were used as control. No differences in body weight and hyperglycemia were observed after transplantation. At 7 months, mice were exposed to a high salt diet (NaCl 4% w/w) for 4 weeks. Db/db-IL1RKO did not develop salt-sensitivity (blood pressure was 110 ± 7 vs. 122 ± 9 mmHg, P&lt;0.05), have less renal IL-6 (138 ± 35 vs. 263 ± 28 pg/mg kidney, P&lt;0.05) and lower ENaC activity (0.4-fold decrease by amiloride test, P&lt;0.05) compared to db/db-WT. In conclusion, our data show that tubular epithelial cells are a major source of IL-1β under high glucose conditions. This cytokine promotes M1 macrophage polarization resulting in higher renal IL-6 levels which increases ENaC activity leading to salt sensitivity.

Immune Mechanisms of Dietary Salt-Induced Hypertension and Kidney Disease: Harry Goldblatt Award for Early Career Investigators 2020.

Salt sensitivity of blood pressure is an independent risk factor for cardiovascular mortality not only in hypertensive but also in normotensive adults. The diagnosis of salt sensitivity of blood pressure is not feasible in the clinic due to lack of a simple diagnostic test, making it difficult to investigate therapeutic strategies. Most research efforts to understand the mechanisms of salt sensitivity of blood pressure have focused on renal regulation of sodium. However, salt retention or plasma volume expansion is not different between salt-sensitive and salt-resistant individuals. In addition, over 70% of extracellular fluid is interstitial and, therefore, not directly controlled by renal salt and water excretion. We discuss in this review how the seminal work by Harry Goldblatt paved the way for our attempts at understanding the mechanisms that underlie immune activation by salt in hypertension. We describe our findings that sodium, entering antigen-presenting cells via an epithelial sodium channel, triggers a PKC (protein kinase C)- and SGK1 (serum/glucocorticoid kinase 1)-stimulated activation of nicotinamide adenine dinucleotide phosphate oxidase, which, in turn, enhances lipid oxidation with generation of highly reactive isolevuglandins. Isolevuglandins adduct to proteins, with the potential to generate degraded peptide neoantigens. Activated antigen-presenting cells increase production of the TH17 polarizing cytokines, IL (interleukin)-6, IL-1β, and IL-23, which leads to differentiation and proliferation of IL-17A producing T cells. Our laboratory and others have shown that this cytokine contributes to hypertension. We also discuss where this sodium activation of antigen-presenting cells may occur in vivo and describe the multiple experiments, with pharmacological antagonists and knockout mice that we used to unravel this sequence of events in rodents. Finally, we describe experiments in mononuclear cells obtained from normotensive or hypertensive volunteers, which confirm that analogous processes of salt-induced immunity take place in humans.

Salt sensitivity of blood pressure in childhood and adolescence.

Although moderation of sodium intake is recommended population-wide, it remains uncertain who benefits from salt restriction. Salt sensitivity refers to changes in blood pressure in response to sodium intake and may occur with or without hypertension. Unfortunately, there is no practical way to assess salt sensitivity in daily practice. Assessment of salt sensitivity even in research studies is challenging with varying protocols utilized which may contribute to differing results. Building on studies in animals and adults, risk factors and conditions associated with salt sensitivity have been identified in the pediatric and young adult populations. This review presents the limited evidence linking obesity, low birth weight, diabetes, chronic kidney disease, and race/ethnicity with salt sensitivity in children, adolescents, and young adults. The impact of stress on sodium handling is also reviewed. The influence of age on the timing of introduction of dietary salt restriction and the long-term influence of salt sensitivity on risk for hypertension are considered. Lastly, interventions other than salt restriction that may improve salt sensitivity and may inform recommendations to families are reviewed.

Advances in Genomics Research of Blood Pressure Responses to Dietary Sodium and Potassium Intakes.

More than half of US adults have hypertension by 40 years of age and a subsequent increase in atherosclerotic cardiovascular disease risk. Dietary sodium and potassium are intricately linked to the pathophysiology of hypertension. However, blood pressure responses to dietary sodium and potassium, phenomena known as salt and potassium sensitivity of blood pressure, respectively, are heterogenous and normally distributed in the general population. Like blood pressure, salt and potassium sensitivity are complex phenotypes, and previous research has shown that up to 75% of individuals experience a blood pressure change in response to such dietary minerals. Previous research has also implicated both high salt sensitivity and low salt sensitivity (or salt resistance) of blood pressure to an increased risk of hypertension and potentially atherosclerotic cardiovascular disease risk. Given the clinical challenges required to accurately measure the sodium and potassium response phenotypes, genomic characterization of these traits has become of interest for hypertension prevention initiatives on both the individual and population levels. Here, we review advances in human genomics research of blood pressure responses to dietary sodium and potassium by focusing on 3 main areas, including the phenotypic characterization of salt sensitivity and resistance, clinical challenges in diagnosing such phenotypes, and the genomic mechanisms that may help to explain salt and potassium sensitivity and resistance. Through this process, we hope to further underline the value of leveraging genomics and broader multiomics for characterizing the blood pressure response to sodium and potassium to improve precision in lifestyle approaches for primordial and primary atherosclerotic cardiovascular disease prevention.

An exploratory analysis of comparative plasma metabolomic and lipidomic profiling in salt-sensitive and salt-resistant individuals from The Dietary Approaches to Stop Hypertension Sodium Trial.

Objective:This study conducted exploratory metabolomic and lipidomic profiling of plasma samples from the DASH (Dietary Approaches to Stop Hypertension) Sodium Trial to identify unique plasma biomarkers to identify salt-sensitive versus salt-resistant participants.Methods:Utilizing plasma samples from the DASH-Sodium Trial, we conducted untargeted metabolomic and lipidomic profiling on plasma from salt-sensitive and salt-resistant DASH-Sodium Trial participants. Study 1 analyzed plasma from 106 salt-sensitive and 85 salt-resistant participants obtained during screening when participants consumed their regular diet. Study 2 examined paired within-participant plasma samples in 20 salt-sensitive and 20 salt-resistant participants during a high-salt and low-salt dietary intervention. To investigate differences in metabolites or lipidomes that could discriminate between salt-sensitive and salt-resistant participants or the response to a dietary sodium intervention Principal Component Analysis and Orthogonal Partial Least Square Discriminant Analysis was conducted. Differential expression analysis was performed to validate observed variance and to determine the statistical significance.Results:Differential expression analysis between salt-sensitive and salt-resistant participants at screening revealed no difference in plasma metabolites or lipidomes. In contrast, three annotated plasma metabolites, tocopherol alpha, 2-ketoisocaproic acid, and citramalic acid, differed significantly between high-sodium and low-sodium dietary interventions in salt-sensitive participants.Conclusion:In DASH-Sodium Trial participants on a regular diet, plasma metabolomic or lipidomic signatures were not different between salt-sensitive and salt-resistant participants. High-sodium intake was associated with changes in specific circulating metabolites in salt-sensitive participants. Further studies are needed to validate the identified metabolites as potential biomarkers that are associated with the salt sensitivity of blood pressure.

Association study of fasting blood glucose and salt sensitivity of blood pressure in community population: The EpiSS study

Background and aimsTo evaluate the association between fasting blood glucose (FBG) and salt sensitivity of blood pressure (SSBP). Methods and resultsThis study is based on the baseline survey of systemic epidemiology of salt sensitivity study. Subjects were classified into salt sensitive (SS) and salt resistant groups according to blood pressure (BP) changes during the modified Sullivan's acute oral saline load and diuresis shrinkage test. Multivariate logistic and linear regression were used to evaluate associations between FBG with SS or BP changes. A total of 2051 participants were included in the analyses with 581 (28.33%) for SS. Multiple analysis showed that for every interquartile range increase in FBG, the OR (95%CI) for SS was 1.140 (1.069, 1.215), β (95%CI) for mean arterial pressure change (ΔMAP1), systolic and diastolic BP changes during saline load were 0.421 (0.221, 0.622), 0.589 (0.263, 0.914) and 0.340 (0.149, 0.531), respectively. Compared to the lowest FBG quartile (Q1), the OR (95%CI) for SS in Q3 and Q4 were 1.342 (1.014, 1.776) and 1.577 (1.194, 2.084), respectively. Compared to subjects with normal FBG, the β (95%CI) for ΔMAP1 was 0.973 (0.055, 1.891) in subjects with impaired FBG, and was 1.449 (0.602, 2.296) in patients with diabetes mellitus. Stratified analyses showed significant and stronger associations between FBG with SSBP in youngers, females, hypertensives, non-diabetics, non-current smokers and non-current drinkers. ConclusionOur findings suggest FBG is an independent, dose-dependent associated factor for SSBP, and prevention of SS focusing on controlling FBG elevation in the early stage is important.

Reduction in Monocyte Isolevuglandins Associated with High Interstitial Sodium Mirrors Salt‐Sensitivity of Blood Pressure in Patients with Essential Hypertension

Salt Sensitivity (SS) of blood pressure (BP) is an independent risk factor for cardiovascular mortality. Sodium (Na+) is stored in skin and muscle interstitium. Antigen presenting cells are activated in response to elevated extracellular Na+ in an ENaC-dependent manner resulting in formation of (isolevuglandin) IsoLG-protein adducts. This leads to T-cell activation, release of inflammatory cytokines, kidney damage, endothelial dysfunction and an increase in BP. We aimed to determine the effect of tissue Na+ storage and immune cell activation on salt-sensitive hypertension. Five subjects with essential hypertension discontinued all anti-hypertensive therapy two weeks before the study. SS was assessed by a rapid inpatient protocol of salt loading (460 mmoL/24 hours) and salt depletion (10 mmoL/24 hours, plus furosemide 40 mg x 3). 23Sodium magnetic resonance imaging was used to measure muscle and skin Na+ contents at baseline (BA). Urine and serum electrolytes, glomerular filtration rate, plasma renin, aldosterone levels, plasma and urine EETs (8-9, 11-12 and 14-15 isoforms) and the percentage of IsoLG adduct-containing CD14+ monocytes via flow cytometry were measured at BA, after salt-loading (HI) and after salt-depletion (LO). All continuous data are displayed as median (interquartile range). Spearman's correlation was used to test associations. 60% of subjects were female, median age was 54 years (44-55), BMI was 35 kg/m2 (30-39), and screening BP was 140/88 mmHg (134-148 / 84-99). The range of the drop in systolic BP from HI to LO (salt-sensitivity index, SSI) was -13.8 to +1.8 mmHg. %isoLG+ CD14+ cells were 48 (27-65) at BA, 55 (31-56) at HI, and 70 (33-72) at LO (p=0.594, by the Kruskal-Wallis test). The correlation between SSI and delta (∆) %isoLGLO minus HI in CD14+ monocytes, was 0.86, [95% confidence interval (CI), -0.07-0.99] (Figure 1A). Skin Na+ content correlated with baseline % IsoLG+ CD14 (r=0.91; 95% CI, 0.12-0.99) (Figure 1B). Higher excretion of urine EETs associated with less IsoLG+ CD14+ cells whereas higher plasma aldosterone per unit urine EET, (a marker of net stimulation of ENaC) associated with a greater number of IsoLG-containing CD14+ cells. No such relationships were observed with plasma EETs. Finally, less stimulation of the aldosterone/urine EET ratio by salt depletion associated with a greater fall in IsoLG+ CD14+ cells (Figure 1C). The change in IsoLG-containing CD14+ monocytes in response to salt depletion appears to be associated with SSBP, which if confirmed in larger number of subjects could constitute a biomarker for SSBP in humans. The association between baseline % of IsoLG-containing CD14+ monocytes and skin Na+ suggests that activation of these cells is due to hyperosmolar Na+ exposure in some interstitial compartment of the body. Relationships between IsoLGs and urine but not plasma EETs suggest that this exposure could be occurring in the hyperosmolar renal medulla.