Sodium-glucose exchanger 2 inhibitor canagliflozin promotes mitochondrial metabolism and alleviates salt-induced cardiac hypertrophy via preserving SIRT3 expression.

INTRODUCTION: Excess salt intake is not only an independent risk factor for heart failure, but also one of the most important dietary factors associated with cardiovascular disease worldwide. Metabolic reprogramming in cardiomyocytes is an early event provoking cardiac hypertrophy that leads to subsequent cardiovascular events upon high salt loading. Although SGLT2 inhibitors, such as canagliflozin, displayed impressive cardiovascular health benefits, whether SGLT2 inhibitors protect against cardiac hypertrophy-related metabolic reprogramming upon salt loading remain elusive. OBJECTIVES: To investigate whether canagliflozin can improve salt-induced cardiac hypertrophy and the underlying mechanisms. METHODS: Dahl salt-sensitive rats developed cardiac hypertrophy by feeding them an 8% high-salt diet, and some rats were treated with canagliflozin. Cardiac function and structure as well as mitochondrial function were examined. Cardiac proteomics, targeted metabolomics and SIRT3 cardiac-specific knockout mice were used to uncover the underlying mechanisms. RESULTS: In Dahl salt-sensitive rats, canagliflozin showed a potent therapeutic effect on salt-induced cardiac hypertrophy, accompanied by lowered glucose uptake, reduced accumulation of glycolytic end-products and improved cardiac mitochondrial function, which was associated with the recovery of cardiac expression of SIRT3, a key mitochondrial metabolic regulator. Cardiac-specific knockout of SIRT3 not only exacerbated salt-induced cardiac hypertrophy but also abolished the therapeutic effect of canagliflozin. Mechanistically, high salt intake repressed cardiac SIRT3 expression through a calcium-dependent epigenetic modifications, which could be blocked by canagliflozin by inhibiting SGLT1-mediated calcium uptake. SIRT3 improved myocardial metabolic reprogramming by deacetylating MPC1 in cardiomyocytes exposed to pro-hypertrophic stimuli. Similar to canagliflozin, the SIRT3 activator honokiol also exerted therapeutic effects on cardiac hypertrophy. CONCLUSION: Cardiac mitochondrial dysfunction caused by SIRT3 repression is a critical promotional determinant of metabolic pattern switching underlying salt-induced cardiac hypertrophy. Improving SIRT3-mediated mitochondrial function by SGLT2 inhibitors-mediated calcium handling would represent a therapeutic strategy against salt-related cardiovascular events.

Increased cerebral vascular resistance underlies preserved cerebral blood flow in response to orthostasis in humans on a high-salt diet.

Cerebral blood flow autoregulation protects brain tissue from blood pressure variations and maintains cerebral perfusion pressure by changes in vascular resistance. High salt (HS) diet impairs endothelium-dependent vasodilation in many vascular beds, including cerebral microcirculation, and may affect vascular resistance. The aim of present study was to determine if 7-day HS diet affected the reactivity of middle cerebral artery (MCA) to orthostatic challenge in healthy human individuals, and if autoregulatory mechanisms and sympathetic neural regulation were involved in this phenomenon.Twenty-seven persons participated in study (F:21, M:6, age range 19-24). Participants consumed 7-day low-salt (LS) diet (< 2.3 g kitchen salt/day) and afterwards 7-day HS diet (> 11.2 g kitchen salt/day). Blood and urine analysis and anthropometric measurements were performed after each diet. Arterial blood pressure, heart rate and heart rate variability, and cerebral and systemic hemodynamic parameters were recorded simultaneously with transcranial Doppler ultrasound and The Task Force® Monitor in response to orthostatic test.Participants remained normotensive during HS diet. Following both, the LS and HS dietary protocols, mean cerebral blood flow (CBF), as well as the velocity time integral and diastolic blood pressure decreased, and cerebral pulsatility index increased after rising up. Importantly, cerebrovascular resistance significantly increased in response to orthostasis only after HS diet. Urine concentration of noradrenaline and vanillylmandelic acid, baroreflex sensitivity (BRS), and sympathetic neural control was significantly decreased in HS diet.Results suggest that CBF in response to orthostatic test was preserved in HS condition due to altered vascular reactivity of MCA, with increased cerebrovascular resistance and blunted BRS and sympathetic activity.

Deleterious effect in endothelin receptor-mediated coronary artery smooth muscle contractility in high-salt diet rats.

BACKGROUND AND AIMS: High-salt diet has been suggested to increase the risk of heart disease. However, the mechanisms underlying coronary artery tension dysfunction caused by high-salt diet are unclear. Previous studies have shown that coronary artery spasm is often induced by endothelin-1 (ET-1) and thromboxane, leading to myocardial ischemia, while the store-operated Ca2+ entry (SOCE) function of coronary smooth muscle is very important in this process. METHODS AND RESULTS: Tension measurements of endothelium-denuded coronary artery ring segments showed that vasocontraction induced by U46619, ET-1, orSTIM1/Orai1-mediated SOCE was significantly lower in 4% high-salt diet rats than in control rats fed a regular diet. The results of western blotting and immunohistochemistry assays showed lower expression levels of endothelial receptors ETA and ETB, STIM1 and Orai1 in coronary artery of high-salt intake rats compared with control rats. Fibrosis was observed by using Masson's trichrome staining and picrosirius red staining. The plasma ET-1 concentration in high-salt diet rats was significantly higher than that of controls. The interventricular septum and posterior wall of high-salt diet rats were significantly thickened. CONCLUSION: Our findings indicated that coronary artery tension was significantly decreased in 4% high-salt diet rats and that this decrease may be due to the change of endothelin receptor and its downstream pathway SOCE related protein expression in coronary artery. Coronary fibrosis was observed in rats fed with high-salt diet. This study provides potential mechanistic insights into high-salt intake-induced heart disease.

Central mechanism of curcumin on the paraventricular hypothalamic nucleus of high salt induced hypertension rats / 中国临床药理学与治疗学

AIM: To assess the effect of curcumin in hypothalamic paraventricular nucleus (PVN) and mean arterial pressure so as to explore the central mechanism of hypertension. METHODS: Sixty Sprague-Dawley rats which body weights between 170 and 190 grams fed with a normal salt (0.3% NaCl) or a high salt (8% NaCl) diet for 6 weeks. Meanwhile half of each team received curcumin administration or vehicle by intragastric administration. Mean Arterial pressure was measured noninvasively via tail-cuff instrument and their recording system. The PVN tissue samPles were collected and stored at −80 °C for later analyses. We performed the following experimental procedures: Western blot analysis, immunofluorescence, immunofluorescence and statistical analysis. RESULTS:The average arterial blood Pressure of rats in the high-salt diet group was significantly reduced after 6 weeks of curcumin intervention. The levels of NOX2, NOX4, TLR4, MyD88, IL-6, IL-1β, MCP-1 and ROS in the long-term high-salt diet grouP were significantly higher after curcumin intervention. CONCLUSION:Curcumin can improve blood pressure in hypertensive rats induced by long-term high salt, the mechanism may be related to the imProvement of oxidative stress and inflammatory cytokines in the paraventricular nucleus of the hypothalamus.

High Salt Intake Induces Active Coping Behaviors by Enhancing the Resilience against Psychological Stress in Mice.

BACKGROUND: High salt intake increases the active coping behavior during psychological stress. Acute fear-related severe stress enhances passive coping behavior during subsequent inescapable stress. METHODS: We investigated the effect of high salt intake (2%) for 5 consecutive days on the coping behavior in C57BL6 mice which employing the tail suspension test (TST) at 1 h after the exposure to inescapable innate fear using 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), a synthetic component of fox feces. By using a different mouse group, to investigated whether anxiety-like behavior was correlated with coping behavior during the TST, we performed the elevated-plus maze (EPM) test at 1 h before the TST without TMT. RESULTS: Both the distance traveled and the number of entries in the central zone of test box during TMT were negatively correlated with freezing time in both sodium- and water-intake mice. Sodium-intake increased the preference for central zone during TMT exposure, but did not change fear sensitivity and locomotor activity. Sodium-intake also prevented that TMT-induced increase in the immobility time during TST. The immobility time during TST was positively correlated with freezing time during TMT exposure in sodium-intake, but not in water-intake mice. Furthermore, the immobility time during TST in sodium-intake mice correlated with the distance traveled and with the number of entries in the central zone during TMT. Sodium intake also increased the number of entries and the time spent in the open arm of the EPM, indicating that high salt intake had an anxiolytic effect. However, neither the number of entries nor the time spent in the open arm of the EPM were correlated with immobility time during TST in sodium-intake mice. CONCLUSIONS: We conclude that a high salt intake induces active coping behavior after experiencing fear stress by enhancing stress resilience rather than by reducing the anxiety level.

High salt intake combined with hypertension elevated the risk of primary liver cancer: a prospective cohort study.

Background: Hypertension and high-salt intake may act synergistically to increase the risk of primary liver cancer (PLC). We prospectively examined the joint effect of hypertension and salt intake on the risk of PLC incidence. Methods: A total of 92,978 participants were included in the final analyses. The study population was divided into 4 groups according to the presence or absence of hypertension and salt intake. Cox proportional hazards regression models were used to evaluate the association of hypertension and/or high-salt intake with the risk of incident cancers. The CAUSALMED procedure was used to perform the mediation analyses. Results: During a median follow-up of 12.69 years, a total of 418 incident cancer cases were identified. Hypertension was a risk factor for PLC in women but not in men. High salt intake was associated with an elevated risk of PLC in men. A significant interaction between salt intake and hypertension was found for the risk of PLC (P for interaction=0.045). Compared with Group 1 (hypertension-, high salt intake-), participants in Group 2 (hypertension-, high salt intake+) and Group 4 (hypertension+, high salt intake+) were associated with an elevated risk of PLC with the corresponding multivariate HRs (95%CIs) of 1.73(0.96,3.10) and 1.96(1.09,3.53) respectively. No significant mediation effect was found for the association between hypertension, salt intake and PLC risk. Conclusions: The combination of high salt intake and hypertension could significantly increase the risk of PLC. It may be reasonable to recommend a low-salt intake to prevent and control the prevalence of PLC and hypertension. Trial registration: Kailuan study, ChiCTR-TNRC-11001489. Registered 24 August, 2011-Retrospectively registered, https://www.chictr.org.cn/showprojen.aspx?proj=8050.

High-Salt Diet Accelerated the Decline of Residual Renal Function in Patients With Peritoneal Dialysis.

Objective: This study aims to investigate the relationship between dietary salt intake and residual renal function in peritoneal dialysis (PD) patients. Methods: The daily salt intake of the patients was calculated based on a 3 day dietary record. Sixty-two patients were divided into three groups: 33 patients in the low salt intake group (salt intake <6.0 g/day), 17 in the medium salt intake group (salt intake 6.0 to <8.0 g/day), and 12 in the high salt intake group (salt intake ≥8.0 g/day). Regular follow-up was conducted every 3 months. Urine volume, peritoneal ultrafiltration volume, and other clinical indicators were recorded. Biochemical indexes were detected to evaluate the changes in residual renal function and peritoneal function during follow-up. Results: A positive correlation between dietary sodium intake and sodium excretion was found. During 12-month follow-up, a decrease of residual renal function showed a significant difference among the three groups (p = 0.041) (15.3 ± 27.5 vs. 12.5 ± 11.5 vs. 32.9 ± 18.4 L/W/1.73 m2 in the low-, medium-, and high salt intake groups, respectively). Consistently, a higher decline of residual renal function (adjusted ß, 20.37; 95% CI, 2.83, 37.91) was found in participants with high salt intake (salt intake ≥8 g/day) compared with those in non-high salt intake. Conclusion: Our study showed that the sodium excretion by peritoneal dialysis was positively correlated with dietary sodium intake in PD patients. The high salt intake diet (salt intake ≥8 g/day) may lead to a faster decline of residual renal function in PD patients.

Biomarkers of high salt intake.

High salt intake is associated with hypertension, which is a leading modifiable risk factor for cardiovascular disease (CVD) and chronic kidney disease (CKD). International Guidelines recommend a large reduction in the consumption of sodium to reduce blood pressure, organ damage, and mortality. In its early stages, the symptoms of CKD are generally not apparent. CKD proceeds in a "silent" manner, necessitating the need for urinary biomarkers to detect kidney damage at an early stage. Since traditional renal biomarkers, such as serum creatinine, are not sufficiently sensitive, difficulties are associated with detecting kidney damage induced by a high salt intake, particularly in normotensive individuals. Several new biomarkers for renal tubular damage, such as neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), vanin-1, liver-type fatty acid-binding protein (L-FABP), and monocyte chemotactic protein-1 (MCP-1), have recently been identified. However, few studies have investigated early biomarkers for CKD progression associated with a high salt diet. This chapter provides insights into novel biomarkers for CKD in normo- and hypertensive individuals with a high salt intake. Recent studies using spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY) fed a high salt diet identified urinary vanin-1 and NGAL as early biomarkers for renal tubular damage in SHR and WKY, whereas urinary KIM-1 was a useful biomarker for salt-induced renal injury in SHR only. Clinical studies are needed to confirm these findings.

Angiotensin II-induced renal angiotensinogen formation is enhanced in mice lacking tumor necrosis factor-alpha type 1 receptor.

In hypertension induced by angiotensin II (AngII) administration with high salt (HS) intake, intrarenal angiotensinogen (AGT) and tumor necrosis factor-alpha (TNF-α) levels increase. However, TNF-α has been shown to suppress AGT formation in cultured renal proximal tubular cells. We examined the hypothesis that elevated AngII levels during HS intake reduces TNF-α receptor type 1 (TNFR1) activity in the kidneys, thus facilitating increased intrarenal AGT formation. The responses to HS diet (4% NaCl) with chronic infusion of AngII (25 ng/min) via implanted minipump for 4 weeks were assessed in wild-type (WT) and knockout (KO) mice lacking TNFR1 or TNFR2 receptors. Blood pressure was measured by tail-cuff plethysmography, and 24-h urine samples were collected using metabolic cages prior to start (0 day) and at the end of 2nd and 4th week periods. The urinary excretion rate of AGT (uAGT; marker for intrarenal AGT) was measured using ELISA. HS +AngII treatment for 4 weeks increased mean arterial pressure (MAP) in all strains of mice. However, the increase in MAP in TNFR1KO (77 ± 2 to 115 ± 3 mmHg; n = 7) was significantly greater (p < 0.01) than in WT (76 ± 1 to 102 ± 2 mmHg; n = 7) or in TNFR2KO (78 ± 2 to 99 ± 5 mmHg; n = 6). The increase in uAGT at 4th week was also greater (p < 0.05) in TNFR1KO mice (6 ± 2 to 167 ± 75 ng/24 h) than that in WT (6 ± 3 to 46 ± 16 ng/24 h) or in TNFR2KO mice (8 ± 7 to 65 ± 44 ng/24 h). The results indicate that TNFR1 exerts a protective role by mitigating intrarenal AGT formation induced by elevated AngII and HS intake.

Comparison of Salt-Related Knowledge and Behaviors Status of WeChat Users between 2019 and 2020.

In order to identify the status of salt-related knowledge and behavior of the residents who were active in WeChat software between 2019 and 2020, 10-day salt-related surveys were conducted in 2019 and 2020 based on the WeChat public platform of China Healthy Lifestyle for All Campaign. Distribution and scores of salt-related knowledge, salt reduction behavior and high-salt intake behavior between 2019 and 2020 were compared. Data of 2109 participants in 2019 and 12,732 participants in 2020 were left for analysis. Overall, 88.2% of participants in 2019 had a willingness to reduce the amount of cooking salt in their households, significantly lower than 90.2% in 2020 (p-value < 0.05). In 2019 and 2020, over 80% of the participants knew fine dried noodles contain salt, but less than 30% knew ice cream contains salt. Over 78% of participants chose 5 g or 6 g for the maximum daily salt intake of healthy adults, and about 98% of participants knew that excessive salt intake would increase the risk of hypertension in both years. The percentage of participants who used salt measuring spoons asked restaurants to use less salt, read the sodium content on the nutrition facts table, chose foods with low sodium content and regularly used low-sodium salt, were 36.1%, 45.0%, 44.1%, 40.3% and 35.8% in 2019, and the percentage increased significantly to 46.4%, 49.2%, 50.8%, 47.1% and 43.4% in 2020 (all p-value < 0.05). The percentage of people regularly eating pickled mustard tubers, salted vegetables and sauce foods or using high-salt condiments also increased from 2019 to 2020. The median of salt-related knowledge scores, salt reduction behavior scores and high-salt intake behavior scores were 11, 2, 5 points in 2019, and 10, 3, 5 points in 2020, respectively. Compared to 2019, the salt-related knowledge score was relatively lower, while the salt reduction behavior score and high-salt intake behavior score were relatively higher in 2020. Besides, the score of salt-related knowledge and behaviors differed in different gender, age and hypertension groups. The COVID-19 epidemic may have influenced the salt-related knowledge and behaviors status of WeChat users in China. Promotion and education of salt-related knowledge and online behavior intervention are still needed, particularly for male and hypertension patients in the future.

The role of salt-inducible kinases on the modulation of renal and intestinal Na+,K+-ATPase activity during short- and long-term high-salt intake.

Type 1 salt-inducible kinases (SIK1) has been shown to act as a mediator during the cellular adaptation to variations in intracellular sodium in a variety of cell types. Type 2 SIK (SIK2) modulates various biological functions and acts as a signal transmitter in various pathways. To evaluate the role of both SIK isoforms in renal and intestinal Na+,K+-ATPase (NKA) activity, we made use of constitutive sik1-/- (SIK1-KO), sik2-/- (SIK2-KO), double sik1-/-sik2-/- (double SIK1*2-KO) knockout and wild-type (WT) mice challenged to a standard (0.3% NaCl) or chronic high-salt (HS, 8% NaCl) diet intake for 48 h or 12 weeks. Long-term HS intake in WT was accompanied by 2-fold increase in jejunal NKA activity and slight (~30% reduction) decreases in NKA in the ileum and cecum; none of these changes was accompanied by changes in the expression of α1-NKA. The ablation of SIK1 and SIK2 prevented the marked increase in jejunal NKA activity following the long-term HS intake. The ablation of SIK1 and SIK2 in mice on a long-term HS intake impacted differently in the ileum and cecum. The most interesting finding is that in SIK2-KO mice marked reductions in NKA activity were observed in the ileum and cecum when compared to WT mice, both on normal and long-term HS intake. In summary, SIK1 or SIK2 ablation on chronic high-salt intake is accompanied by modulation of NKA along the intestinal tract, which differ from those after an acute high-salt intake, and this may represent an absorptive compensatory mechanism to keep electrolyte homeostasis.

Gut Dysbiosis and Western Diet in the Pathogenesis of Essential Arterial Hypertension: A Narrative Review.

Metabolic syndrome is a cluster of the most dangerous cardiovascular (CV) risk factors including visceral obesity, insulin resistance, hyperglycemia, alterations in lipid metabolism and arterial hypertension (AH). In particular, AH plays a key role in the complications associated with metabolic syndrome. High salt intake is a well-known risk factor for AH and CV diseases. Vasoconstriction, impaired vasodilation, extracellular volume expansion, inflammation, and an increased sympathetic nervous system (SNS) activity are the mechanisms involved in the pathogenesis of AH, induced by Western diet. Gut dysbiosis in AH is associated with reduction of short chain fatty acid-producing bacteria: acetate, butyrate and propionate, which activate different pathways, causing vasoconstriction, impaired vasodilation, salt and water retention and a consequent high blood pressure. Moreover, increased trimethylamine N-oxide and lipopolysaccharides trigger chronic inflammation, which contributes to endothelial dysfunction and target organs damage. Additionally, a high salt-intake diet impacts negatively on gut microbiota composition. A bidirectional neuronal pathway determines the "brain-gut" axis, which, in turn, influences blood pressure levels. Then, we discuss the possible adjuvant novel treatments related to gut microbiota modulation for AH control.

Antagonistic modulation of SIK1 and SIK2 isoforms in high blood pressure and cardiac hypertrophy triggered by high-salt intake.

Salt-inducible kinases (SIKs) represent a subfamily of AMPK family kinases. SIK1 has been shown to act as a mediator during the cellular adaptation to variations in intracellular sodium in a variety of cell types. SIK2, as an isoform of the SIK family, modulates various biological functions and acts as a signal transmitter in various pathways. To evaluate the role of both SIK1 and SIK2 isoforms in blood pressure (BP), body fluid regulation and cardiac hypertrophy development, we made use of constitutive sik1-/- (SIK1-KO), sik2-/- (SIK2-KO), double sik1-/-sik2-/- (double SIK1*2-KO) knockout and wild-type (WT) mice challenged to a standard (0.3% NaCl) or chronic high-salt (HS, 8% NaCl) diet intake for 12 weeks.Mice, under a standard diet intake, had similar and normal BP. On a chronic HS intake, SIK1-KO and double SIK1*2-KO mice showed increased BP, but not WT and SIK2-KO mice. A chronic HS intake led to the development of cardiac left ventricle hypertrophy (LVH) in normotensive WT and hypertensive SIK1-KO mice, but not in SIK2-KO mice. Double SIK1*2-KO mice under standard diet intake show normal BP but an increased LV mass. Remarkably, in response to a dietary stress condition, there is an increase in BP but LVH remained unchanged in double SIK1*2-KO mice.In summary, SIK1 isoform is required for maintaining normal BP in response to HS intake. LVH triggered by HS intake requires SIK2 isoform and is independent of high BP.

Physical interaction of tropomyosin 3 and STIM1 regulates vascular smooth muscle contractility and contributes to hypertension.

SCOPE: Tropomyosin (TPM), an actin-binding protein widely expressed across different cell types, is primarily involved in cellular contractile processes. We investigated whether TPM3 physically and functionally interacts with stromal interaction molecule 1 (STIM1) to contribute to vascular smooth muscle cell (VSMC) contraction, store-operated calcium entry (SOCE), and high-salt intake-induced hypertension in rats. METHODS AND RESULTS: Analysis of a rat RNA-seq data set of 80 samples showed that the STIM1 and Tpm3 transcriptome expression pattern is highly correlated, and co-immunoprecipitation results indicated that TPM3 and STIM1 proteins physically interacted in rat VSMCs. Immunohistochemical data displayed obvious co-localization of TPM3 and STIM1 in rat VSMCs. Knockdown of TPM3 or STIM1 in VSMCs with specific small interfering RNA significantly suppressed contractions in tension measurement assays and decreased SOCE in calcium assays. Rats fed a high-salt diet for 4 weeks had significantly higher systolic blood pressure than controls, with significantly increased contractility and markedly increased TPM3 and STIM1 expression levels in the mesenteric resistance artery (shown by tension measurements and immunoblotting, respectively). Additionally, high salt environment in vitro induced significant enhancement of TPM3 and STIM1 expression levels in VSMCs. CONCLUSIONS: We showed for the first time that TPM3 and STIM1 physically and functionally interact to contribute to VSMC contraction, SOCE, and high-salt intake-induced hypertension. Our findings provide mechanistic insights and offer a potential therapeutic target for high-salt intake-induced hypertension.

High-salt intake reduces renal tissue levels of inflammatory cytokines in mice.

High salt (HS) intake is usually considered as an aggravating factor to induce inflammatory renal injury. However, the changes in the renal levels of inflammatory cytokines during HS intake is not yet clearly defined. We hypothesize that HS increases renal levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) but decreases interleukin-10 (IL-10; anti-inflammatory cytokine) and these responses exacerbate in NO deficient conditions. Both wild-type (WT) and endothelial NO synthase knockout (eNOSKO) mice (~8 weeks old, n = 6 in each group) were given normal-salt (NS; 0.3% NaCl) and HS (4% NaCl) containing diets for 2 weeks. Systolic blood pressure (SBP) was determined by tail-cuff plethysmography and urine collections were made using metabolic cages. Basal SBP was higher in eNOSKO than WT mice (131 ± 7 vs 117 ± 3 mmHg; p < .05). HS intake for 2 weeks increased SBP in eNOSKO (161 ± 5 mmHg) but not in WT mice. In NS groups, the cytokine levels in renal tissues (measured using ELISA kits and expressed in pg/mg protein) were significantly higher in eNOSKO than WT mice (TNF-α, 624 ± 67 vs. 325 ± 73; IL-6, 619 ± 106 vs. 166 ± 61; IL-10, 6,087 ± 567 vs. 3,929 ± 378). Interestingly, these cytokine levels in HS groups were significantly less both in WT (TNF-α, 114 ± 17; IL-6, 81 ± 14; IL-10, 865 ± 130) and eNOSKO (TNF-α, 115 ± 18; IL-6, 56 ± 7; IL-10, 882 ± 141) mice. These findings indicate that HS induces downregulation of cytokines in the kidney. Such HS-induced reduction in cytokines, particularly TNF-α (a natriuretic agent), would facilitate more salt-retention, and thus, leading to salt-sensitive hypertension in NO deficient conditions.

Differentially expressed transcripts and associated protein pathways in basilar artery smooth muscle cells of the high-salt intake-induced hypertensive rat.

The pathology of cerebrovascular disorders, such as hypertension, is associated with genetic changes and dysfunction of basilar artery smooth muscle cells (BASMCs). Long-term high-salt diets have been associated with the development of hypertension. However, the molecular mechanisms underlying salt-sensitive hypertension-induced BASMC modifications have not been well defined, especially at the level of variations in gene transcription. Here, we utilized high-throughput sequencing and subsequent signaling pathway analyses to find a two-fold change or greater upregulated expression of 203 transcripts and downregulated expression of 165 transcripts in BASMCs derived from rats fed a high-salt diet compared with those from control rats. These differentially expressed transcripts were enriched in pathways involved in cellular, morphological, and structural plasticity, autophagy, and endocrine regulation. These transcripts changes in the BASMCs derived from high-salt intake-induced hypertensive rats may provide critical information about multiple cellular processes and biological functions that occur during the development of cerebrovascular disorders and provide potential new targets to help control or block the development of hypertension.

Depletion of C1 neurons attenuates the salt-induced hypertension in unanesthetized rats.

High salt intake is able to evoke neuroendocrine and autonomic responses that include vasopressin release and sympathoexcitation resulting in increasing in the arterial blood pressure (BP). The C1 neurons are a specific population of catecholaminergic neurons located in the RVLM region and they control BP under homeostatic imbalance. Thus, here we hypothesized that the ablation of C1 neurons mitigate the high blood pressure induced by high-salt intake. To test this hypothesis, we injected anti-DßH-SAP saporin at the RVLM and monitored the BP in unanesthetized animals exposed to high salt intake of 2% NaCl solution for 7 days. The injection of anti-DßH-SAP into the RVLM depleted 80% of tyrosine hydroxylase-positive neurons (TH+ neurons) in the C1, 38% in the A5, and no significant reduction in the A1 region, when compared to control group (saline as vehicle). High salt intake elicited a significant increase in BP in the control group, while in the anti-DßH-SAP group the depletion of TH+ neurons prevents the salt-induced hypertension. Moreover, the low frequency component of systolic BP and pulse interval were increased by high-salt intake in control animals but not in anti-DßH-SAP group, which indirectly suggests that the increase in the BP is mediated by increase in sympathetic activity. In conclusion, our data show that hypertension induced by high-salt intake is dependent on C1 neurons.

High Salt Intake Impairs Erectile Function in Salt-Sensitive Rats Through Mineralocorticoid Receptor Pathway Beyond Its Effect on Blood Pressure.

BACKGROUND: High salt intake is a risk factor for hypertension, which can potentially lead to erectile dysfunction (ED); however, the underlying pathological mechanisms remain unclear. AIM: To investigate whether erectile function is directly impaired by high salt intake and whether selective inhibition of mineralocorticoid receptor (MR) could provide protection from ED. METHODS: 6-week-old male Dahl salt-sensitive rats were randomly divided into 3 groups: normal diet (0.3% NaCl; control, n = 8), high-salt diet (8% NaCl; HS, n = 8), and high-salt diet plus eplerenone (HS + EPL, n = 11). HS + EPL rats were orally administered daily doses of EPL (75 mg/kg) for 6 weeks; control and HS rats received purified water on the same schedule. OUTCOMES: At the end of the study period, erectile function was evaluated by measuring intracavernosal pressure and mean arterial pressure after cavernous nerve stimulation. Serum levels of asymmetric dimethylarginine and L-arginine were determined using ultraperformance liquid chromatography-tandem mass spectrometry. Quantitative PCR was used to assess the expression of MR, inflammation, and oxidative stress markers (nicotinamide adenine dinucleotide phosphate oxidase-1/4, p22phox, interleukin-6, and superoxide dismutase-1), and protein arginine N-methyltransferase-1. RESULTS: The intracavernosal pressure/mean arterial pressure ratio was significantly lower, whereas systolic blood pressure, MR expression, serum asymmetric dimethylarginine levels, oxidative stress, and levels of inflammatory biomarkers were significantly higher in HS rats than in control rats (P < .05). EPL administration significantly improved each of these parameters except systolic blood pressure and MR expression. No significant intergroup differences were observed for L-arginine and superoxide dismutase-1 levels. CLINICAL TRANSLATION: Our results provide a rationale for the need of salt restriction and the use of selective MR inhibitors in prophylaxis or treatment of ED in men consuming a high-salt diet. STRENGTHS & LIMITATIONS: We are the first to report that the adverse impact of high salt intake on erectile function is mediated via MR activation, independent of its effect on blood pressure. A major limitation of this study is that responses of salt-resistant rats were not studied. CONCLUSIONS: High salt intake directly impaired erectile function in Dahl salt-sensitive rats, whereas selective MR inhibition ameliorated this effect. Kishimoto T, Kataoka T, Yamamoto Y, et al. High Salt Intake Impairs Erectile Function in Salt-Sensitive Rats Through Mineralocorticoid Receptor Pathway Beyond Its Effect on Blood Pressure. J Sex Med 2020;17:1280-1287.

High Salt Diet Affects the Reproductive Health in Animals: An Overview.

Salinity is a reliable issue of crop productivity loss in the world and in certain tropical and subtropical zones. However, tremendous progress in the genetic improvement of plants for salinity tolerance has been made over several decades. In light of this, halophytic plants can be used as animal feeds and have promising features because they are a good feed resource. However, the main constraint of saline pasture systems is the extreme concentration of NaCl salt in drinking water and forage plants for grazing animals. Ecological reports revealed that excess diet salt causes mortality and morbidity worldwide. Animal fed halophytic forages may have adverse effects on growth performance and reproductive function in males and females due to inducing reductions in hormone regulation, such as testosterone, FSH, LH, and leptin. It was indicated that high salt intake promotes circulating inflammatory factors in the placenta and is associated with adversative effects on pregnancy. This review focuses on the scientific evidence related to the effect of high salt intake on growth performance, spermatogenesis, sperm function, and testicular morphology changes in male animals. In addition, the review will also focus on its effect on some female reproductive features (e.g., ovarian follicle developments, placental indices, and granulosa cell function).

Relationship between the intake of salt and salted food and the infection of Helicobacter pylori in 40-69 years old local residents in a county with high gastric cancer risk in Anhui Province / 中华疾病控制杂志

Objective The aim of the present study was to investigate the relationship between the intake of salt and salted food and the infection of Helicobacter pylori (Hp) among 40-69 years old local residents in a county with high gastric cancer risk in Anhui province. Methods From July 2015 to August 2018, we conducted a questionnaire and a serological test for Hp among 40-69 years old local residents in Lujiang county, Anhui province. The questionnaire focused on the consumptions of salt and salted food. The relationship between Hp infection and risk factors was analyzed by gender. Univariate and multivariate logistic regression analysis were used to analyze the relevant influencing factors. Results The Hp infection rate of total local residents was 50.07%. Among male subjects, age, body mass index(BMI), marital status, educational level, job, labor intensity and income had no link to Hp infection (all P>0.05). But among female subjects, BMI was associated with Hp infection ( 2=13.454,P=0.001). Besides, alcohol consumption was a risk factor for Hp infection in male subjects(OR=1.789，95% CI:1.188-2.694，P=0.003). But, high intake of salt and salted food had no effect on Hp infection after adjustment for alcohol consumption variable in men using multivariate analysis (all P>0.05). After adjusted for BMI variable among female individuals, high salt intake (≥9 g/day) (OR=1.462，95% CI:1.060-2.015，P=0.021) and the high salted food intake (≥1 times /day) were risk factors for Hp infection in women(OR=1.560，95% CI:1.021-2.383，P=0.040). Conclusions In one county with high gastric cancer risk in Anhui province, high salt intake (≥9 g/day) and high salted food intake (≥1 times/day) are risk factors for Hp infection among 40-69 years old female local residents.