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This review highlights the molecular basis of salt sensitivity in hypertension, with a focus on the regulation of sodium transport in the distal nephron. Sodium reabsorption in this region is often linked to the actions of aldosterone, although in recent years numerous findings have been reported on the aldosterone-independent pathway of acquiring salt sensitivity by potassium deficiency or potassium loading. The key to this discussion is the interplay, through extracellular potassium concentration, between the first part of the tubules expressing the Na+-Cl− cotransporter (NCC) and the second part expressing the epithelial Na+ channel (ENaC). The molecular pathways such as with-no-lysine 1 (WNK)-STE20/SPS1-related proline-alanine-rich kinase (SPAK)/oxidative stress-responsive kinase 1 (OSR1) signaling, Kelch-like family member 3 (KLHL3)-cullin 3 (CUL3) complex, protein phosphatases, and mechanistic target of rapamycin complex 2 (mTORC2)-Nedd4L pathway are described as the mechanism by which salt sensitivity on blood pressure is acquired in response to changes in physiological conditions including potassium depletion or loading. This review highlights the potential for targeting these molecular pathways to develop novel therapeutic strategies for the treatment of salt-sensitive hypertension, the mechanism of which remains to be elucidated. [ABSTRACT FROM AUTHOR]

BACKGROUND Salt-sensitive hypertension is often more prone to induce damage to target organs such as the heart and kidneys. Abundant recent studies have demonstrated a close association between ferroptosis and cardiovascular diseases. Therefore, we hypothesize that ferroptosis may be closely associated with organ damage in salt-sensitive hypertension. This study aimed to investigate whether ferroptosis is involved in the occurrence and development of myocardial fibrosis and renal fibrosis in salt-sensitive hypertensive rats. METHODS Ten 7-week-old male Dahl salt-sensitive (Dahl-SS) rats were adaptively fed for 1 week, then randomly divided into two groups and fed either a normal diet (0.3% NaCl, normal diet group) or a high-salt diet (8% NaCl, high-salt diet group) for 8 weeks. Blood pressure of the rats was observed, and analysis of the hearts and kidneys of Dahl-SS rats was conducted via hematoxylin-eosin (HE) staining, Masson staining, Prussian blue staining, transmission electron microscopy, tissue iron content detection, malondialdehyde content detection, immunofluorescence, and Western blot. RESULTS Compared to the normal diet group, rats in the high-salt diet group had increases in systolic blood pressure and diastolic blood pressure (P  < 0.05); collagen fiber accumulation was observed in the heart and kidney tissues (P  < 0.01), accompanied by alterations in mitochondrial ultrastructure, reduced mitochondrial volume, and increased density of the mitochondrial double membrane. Additionally, there were significant increases in both iron content and malondialdehyde levels (P  < 0.05). Immunofluorescence and Western blot results both indicated significant downregulation (P  < 0.05) of xCT and GPX4 proteins associated with ferroptosis in the high-salt diet group. CONCLUSIONS Ferroptosis is involved in the damage and fibrosis of the heart and kidney tissues in salt-sensitive hypertensive rats. [ABSTRACT FROM AUTHOR]

BACKGROUND Hypertension is a risk factor for atrial fibrillation (AF), and brain and muscle arnt-like protein 1 (Bmal1) regulate circadian blood pressure and is implicated in several fibrotic disorders. Our hypothesis that Bmal1 inhibits atrial fibrosis and susceptibility to AF in salt-sensitive hypertension (SSHT) and our study provides a new target for the pathogenesis of AF induced by hypertension. METHODS The study involved 7-week-old male Dahl salt-sensitive that were fed either a high-salt diet (8% NaCl; DSH group) or a normal diet (0.3% NaCl; DSN group). An experimental model was used to measure systolic blood pressure (SBP), left atrial ejection fraction (LAEF), left atrial end-volume index (LAEVI), left atrial index (LAFI), AF inducibility, AF duration, and atrial fibrosis pathological examination and the expression of Baml1 and fibrosis-related proteins (TNF-α and α-SMA) in left atrial tissue. RESULTS DSH increased TNF-α and α-SMA expression in atrial tissue, level of SBP and LAESVI, atrial fibrosis, AF induction rate, and AF duration, and decreased Bmal1 expression in atrial tissue, the circadian rhythm of hypertension, and level of LAEF and LAFI. Our results also showed that the degree of atrial fibrosis was negatively correlated with Bmal1 expression, but positively correlated with the expression of TNF-α and α-SMA. CONCLUSIONS We demonstrated that a high-salt diet leads to circadian changes in hypertension due to a reduction of Bmal1 expression, which plays a crucial role in atrial fibrosis and increased susceptibility to AF in SSHT rats. [ABSTRACT FROM AUTHOR]

BACKGROUND High salt (HS) intake induces an augmented hypertensive response to nitric oxide (NO) inhibition, though it causes minimal changes in blood pressure (BP) in NO intact condition. The cause of such augmentation is not known. HS induces tumor necrosis factor-alpha (TNFα) production that causes natriuresis via activation of its receptor type 1 (TNFR1). We hypothesized that NO deficiency reduces renal TNFR1 activity, leading to enhanced sodium retention and hypertension. METHODS We examined the changes in renal TNFR1 protein expression (Immunohistochemistry analyses) after HS (4% NaCl) intake in wild-type mice (WT, C57BL6) treated with a NO synthase (NOS) inhibitor, nitro- l -arginine methyl ester (L-NAME; 0.05 mg/min/g; osmotic mini-pump), as well as in endothelial NOS knockout mice (eNOSKO) and compared the responses in WT mice with normal salt (NS; 0.3% NaCl) intake. BP was measured with tail-cuff plethysmography and 24-hour urine collections were made using metabolic cages. RESULTS HS alone did not alter mean BP in untreated mice (76 ± 3 to 77 ± 1 mm Hg) but induced an augmented response in L-NAME treated (106 ± 1 vs. 97 ± 2 mm Hg) and in eNOSKO (107 ± 2 vs. 89 ± 3 mm Hg) mice. The percentage area of TNFR1 expression in renal tissue was higher in WT + HS (4.1 + 0.5%) than in WT + NS mice (2.7 ± 0.6%). However, TNFR1 expression was significantly lower in L-NAME treated WT + NS (0.9 ± 0.1%) and in eNOSKO + NS (1.4 ± 0.2%) than in both WT + NS and WT + HS mice. CONCLUSIONS These data indicate that TNFR1 activity is downregulated in NO deficient conditions, which facilitates salt retention leading to augmented hypertension during HS intake. [ABSTRACT FROM AUTHOR]

Hypertension affects approximately one in two United States adults and sex plays an important role in the pathogenesis of hypertension. The Na+-Cl− cotransporter (NCC), regulated by a kinase network including with-no-lysine kinase (WNK)1 and WNK4, STE20/SPS1-related proline alanine-rich kinase (SPAK), and oxidative stress response 1 (OxSR1), is critical to Na+ reabsorption and blood pressure regulation. Dietary salt differentially modulates NCC in salt-sensitive and salt-resistant rats, in part by modulation of WNK/SPAK/OxSR1 signaling. In this study, we tested the hypothesis that sex-dependent differences in NCC regulation contribute to the development of the salt sensitivity of blood pressure using male and female Sprague-Dawley (SD), Dahl salt-resistant (DSR), and Dahl salt-sensitive (DSS) rats. In normotensive salt-resistant SD and DSR rats, a high-salt diet evoked significant decreases in NCC activity, expression, and phosphorylation. In males, these changes were associated with no change in WNK1 expression, a decrease in WNK4 levels, and suppression of SPAK/OxSR1 expression and phosphorylation. In contrast, in females, there was decreased NCC activity associated with suppression of SPAK/OxSR1 expression and phosphorylation. In hypertensive DSS rats, the ability of females to suppress NCC (in opposition to males) via a SPAK/OxSR1 mechanism likely contributes to their lower magnitude of salt-sensitive hypertension. Collectively, our findings support the existence of sex differences in male versus female rats with NCC regulation during dietary salt intake involving suppression of WNK4 expression in male rats only and the involvement of SPAK/OxSR1 signaling in both males and females. NEW & NOTEWORTHY: NCC regulation is sex dependent. In normotensive male and female Sprague-Dawley and Dahl salt-resistant rats, which exhibit dietary Na+-evoked NCC suppression, male rats exhibit decreased WNK4 expression and decreased SPAK and OxSR1 levels, whereas female rats only suppress SPAK and OxSR1. In hypertensive Dahl salt-sensitive rats, the ability of females to suppress NCC (in opposition to males) via a SPAK/OxSR1 mechanism likely contributes to their lower magnitude of salt-sensitive hypertension. [ABSTRACT FROM AUTHOR]

Salt‐sensitive hypertension is common among individuals with essential hypertension, and the prevalence of left ventricular hypertrophy (LVH) has increased. However, data from early identification of the risk of developing LVH in young adults with salt‐sensitive hypertension are lacking. Thus, the present study aimed to design a nomogram for predicting the risk of developing LVH in young adults with salt‐sensitive hypertension. A retrospective analysis of 580 patients with salt‐sensitive hypertension was conducted. The training set consisted of 70% (n = 406) of the patients, while the validation set consisted of the remaining 30% (n = 174). Based on multivariate analysis of the training set, predictors for LVH were extracted to develop a nomogram. Discrimination curves, calibration curves, and clinical utility were employed to assess the predictive performance of the nomogram. The final simplified nomogram model included age, sex, office systolic blood pressure, duration of hypertension, abdominal obesity, triglyceride‐glucose index, and estimated glomerular filtration rate (eGFR). In the training set, the model demonstrated moderate discrimination, as indicated by an area under the receiver operating characteristic (ROC) curve of 0.863 (95% confidence interval: 0.831–0.894). The calibration curve exhibited good agreement between the predicted and actual probabilities of LVH in the training set. Additionally, the validation set further confirmed the reliability of the prediction nomogram. In conclusions, the simplified nomogram, which consists of seven routine clinical variables, has shown good performance and clinical utility in identifying young adults with salt‐sensitive hypertension who are at high risk of LVH at an early stage. [ABSTRACT FROM AUTHOR]

Abstract Salt‐sensitive hypertension is common among individuals with essential hypertension, and the prevalence of left ventricular hypertrophy (LVH) has increased. However, data from early identification of the risk of developing LVH in young adults with salt‐sensitive hypertension are lacking. Thus, the present study aimed to design a nomogram for predicting the risk of developing LVH in young adults with salt‐sensitive hypertension. A retrospective analysis of 580 patients with salt‐sensitive hypertension was conducted. The training set consisted of 70% (n = 406) of the patients, while the validation set consisted of the remaining 30% (n = 174). Based on multivariate analysis of the training set, predictors for LVH were extracted to develop a nomogram. Discrimination curves, calibration curves, and clinical utility were employed to assess the predictive performance of the nomogram. The final simplified nomogram model included age, sex, office systolic blood pressure, duration of hypertension, abdominal obesity, triglyceride‐glucose index, and estimated glomerular filtration rate (eGFR). In the training set, the model demonstrated moderate discrimination, as indicated by an area under the receiver operating characteristic (ROC) curve of 0.863 (95% confidence interval: 0.831–0.894). The calibration curve exhibited good agreement between the predicted and actual probabilities of LVH in the training set. Additionally, the validation set further confirmed the reliability of the prediction nomogram. In conclusions, the simplified nomogram, which consists of seven routine clinical variables, has shown good performance and clinical utility in identifying young adults with salt‐sensitive hypertension who are at high risk of LVH at an early stage.

The endothelial glycocalyx is closely associated with various physiological and pathophysiological events. Significant modification of the endothelial glycocalyx is an early process in the pathogenesis of cardiovascular disease. High dietary salt and HIV infection damages the endothelial glycocalyx causing endothelial dysfunction and increasing the risk for salt-sensitive hypertension and cardiovascular disease. The two factors, HIV infection and dietary salt are critical independent predictors of hypertension and cardiovascular disease and often synergize to exacerbate and accelerate disease pathogenesis. Salt-sensitive hypertension is more common among people living with HIV and is associated with risk for cardiovascular disease, stroke, heart attack and even death. However, the underlying mechanisms linking endothelial glycocalyx damage to dietary salt and HIV infection are lacking. Yet, both HIV infection/treatment and dietary salt are closely linked to endothelial glycocalyx damage and development of saltsensitive hypertension. Moreover, the majority of individuals globally, consume more salt than is recommended and the burden of HIV especially in sub-Sahara Africa is disproportionately high. In this review, we have discussed the missing link between high salt and endothelial glycocalyx shedding in the pathogenesis of salt-sensitive hypertension. We have further elaborated the role played by HIV infection and treatment in modifying endothelial glycocalyx integrity to contribute to the development of hypertension and cardiovascular disease. [ABSTRACT FROM AUTHOR]

Dahl salt‐sensitive (SS) rats fed a high‐salt diet, but not low‐salt, exhibit vascular dysfunction. Several substrains of SS rats exist that differ in their blood pressure phenotypes and salt sensitivity. The goal of this study was to investigate whether the John‐Rapp‐derived SS rat (SS/Jr), which exhibits spontaneous hypertension on a low‐salt diet, presents with hallmarks of vascular dysfunction observed in another experimental model of hypertension independent of dietary salt, the spontaneously hypertensive rat (SHR). Endothelium‐intact aortic rings and mesenteric resistance arteries were isolated from low‐salt fed adult male SS/Jr rats and SHRs, or their respective controls, for isometric wire myography. Vessels were challenged with cumulative concentrations of various vasoactive substances, in the absence or presence of nitric oxide synthase or cyclooxygenase inhibitors. Despite showing some differences in their responses to various vasoactive substances, both SS/Jr rats and SHRs exhibited key features of vascular dysfunction, including endothelial dysfunction and hyperresponsiveness to vasocontractile agonists. In conclusion, this study provides evidence to support the utility of the SS/Jr rat strain maintained on a low‐salt diet as a valid experimental model for vascular dysfunction, a key feature of human hypertension. [ABSTRACT FROM AUTHOR]

Background: Buyang Huanwu decoction (BHD) is a traditional Chinese medicine herbal formula used for treating hypertension, particularly in the later stages of hypertension when it is associated with intracerebral hemorrhage. This study aims to investigate the treatment mechanism of BHD to provide a basis for its clinical application in hypertension treatment. Methods: Network pharmacology analysis and cell culture experiments were performed to explore the potential proteins and mechanisms of action of BHD against hypertension. Bioactive compounds related to BHD were screened, and relevant targets associated with hypertension and BHD were retrieved. Molecular docking technology was used to identify the effective signaling pathway based on the Kyoto Encyclopedia of Genes and Genomes and protein-protein interaction network cores. Lastly, the effects and mechanisms of BHD on salt-sensitive hypertensive endothelial cells were investigated. Results: Ninety-three potential therapeutic targets for BHD and salt-sensitive hypertension were found to be closely associated with the PI3K/Akt/eNOS signaling pathway and oxidative stress. Cell experiments further indicated the pivotal role of endothelial cells in hypertension, and validation analysis showed that BHD significantly preserved cell morphology, suppressed oxidative stress reactions, activated the PI3K/Akt/eNOS signaling pathways, preserved normal endothelial cell function, and reduced cell apoptosis. Conclusion: BHD effectively activates the PI3K/Akt/VEGF signaling pathway, attenuates oxidative stress-induced injury in endothelial cells exposed to high salt levels, and mitigates apoptosis, supporting the use of traditional Chinese medicine BHD in the treatment of salt-sensitive hypertension. [ABSTRACT FROM AUTHOR]

Background: Long term hypertension seriously promotes target organ damage in the brain and heart, and has increasingly become serious public health problem worldwide. The anti-hypertensive effects of capsaicin has been reported, however, the role and mechanism of capsaicin within the brain on salt-induced hypertension have yet to be elucidated. This study aimed to verify the hypothesis that capsaicin attenuates salt-induced hypertension via the AMPK/Akt/Nrf2 pathway in hypothalamic paraventricular nucleus (PVN). Methods: Dahl salt-sensitive (Dahl S) rats were used as animal model for the present study. Rats were randomly divided into four groups based on their dietary regimen (0.3% normal salt diet and 8% high salt diet) and treatment methods (infusion of vehicle or capsaicin in the PVN). Capsaicin was chronically administered in the PVN throughout the animal experiment phase of the study that lasted 6 weeks. Results: Our results demonstrated that PVN pretreatment with capsaicin can slow down raise of the blood pressure elevation and heart rate (HR) of Dahl S hypertensive rats given high salt diet. Interestingly, the cardiac hypertrophy was significantly improved. Furthermore, PVN pretreatment with capsaicin induced decrease in the expression of mRNA expression of NADPH oxidase-2 (NOX2), inducible nitric oxide synthase (iNOS), NOX4, p-IKKß and proinflammatory cytokines and increase in number of positive cell level for Nrf2 and HO-1 in the PVN of Dahl S hypertensive rats. Additionally, the protein expressions of phosphatidylinositol 3-kinase (p-PI3K) and phosphorylated protein kinase-B (p-AKT) were decreased, phosphorylated adenosine monophosphate-activated protein kinase (p-AMPK) were increased after the PVN pretreatment with capsaicin. Conclusion: Capsaicin pretreatment attenuates salt-sensitive hypertension by alleviating AMPK/Akt/iNOS pathway in the PVN. [ABSTRACT FROM AUTHOR]

Objectives: Prolonged exposure to chronic hypertension places the heart under excessive strain, resulting in myocardial remodeling. Phillyrin, derived from the natural plant Forsythia suspensa, has been found to possess cardioprotective properties. The objective of this study is to investigate the role and mechanism of phillyrin in hypertension-induced myocardial remodeling in mice. Methods: We constructed a mouse model of salt-sensitive hypertension. The mice were treated with varying doses of phillyrin, and their blood pressure, cardiac function, cardiac hypertrophy, fibrosis, inflammation, and other conditions were assessed. Key findings: Our research findings demonstrated that phillyrin has the potential to lower blood pressure, enhance cardiac function, and mitigate cardiac hypertrophy, fibrosis, and inflammatory responses in deoxycorticosterone acetate-salt hypertension mice. In hypertensive mice, there was an elevated expression of endothelin1 (ET-1) in heart tissue, which can be reduced by phillyrin. Additionally, phillyrin effectively reduced the hypertrophy of H9c2 cells induced by ET-1 stimulation. Conclusions: Our research highlights the therapeutic capabilities of phillyrin in the treatment of myocardial remodeling through the reduction of ET-1 signaling. These results contribute to the advancement of novel applications for phillyrin and establish a solid conceptual basis for future investigations in this area. [ABSTRACT FROM AUTHOR]

As a resistant hypertension, the pathogenesis of salt-sensitive hypertension is complex. Although mineralocorticoid receptor activation and renal injury play a key role in the development of salt-sensitive hypertension, the specific pathological mechanism is currently unclear. A model of Dahl SS hypertension was established by high-salt diet induction to explore the pathological mechanism of salt-sensitive hypertension and kidney injury. Compared with salt-insensitive SS-13BN rats, long-term high-salt diet caused local activation of sympathetic nerves and renin-angiotensin-aldosterone system (RAAS) in the kidney of Dahl SS rats, which eventually activated mineralocorticoid receptors (MR), resulting in the increased expression of epithelial sodium channels (ENaC), enhanced inflammatory response and oxidative stress, renal fibrosis, and triggered the increased expression of phosphorylated actin (P-Cofilin) and podocin in the kidney, resulting in podocyte damage and ultimately renal injury and hypertension. [ABSTRACT FROM AUTHOR]

Background Irisin, as a myokine, plays a protective role against cardiovascular disease, including myocardial infarction, atherosclerosis and hypertension. However, whether irisin attenuates salt-sensitive hypertension and the related underlying mechanisms is unknown.Methods Male Dahl salt-resistant (DSR) and Dahl salt-sensitive (DSS) (12 weeks) rats were fed a high salt diet (8% NaCl) with or without irisin treatment by intraperitoneal injection for 8 weeks.Results Compared with DSR rats, DSS rats showed higher systolic blood pressure (SBP), impaired natriuresis and diuresis and renal dysfunction. In addition, it was accompanied by downregulation of renal p-AMPKα and upregulation of renal RAC1 and nuclear mineralocorticoid receptor (MR). Irisin intervention could significantly up-regulated renal p-AMPKα level and down-regulated renal RAC1-MR signal, thereby improving renal sodium excretion and renal function, and ultimately reducing blood pressure in DSS rats. Ex vivo treatment with irisin reduced the expression of RAC1 and nuclear MR in primary renal distal convoluted tubule cells from DSS rats and the effects of irisin were abolished by cotreatment of compound C (AMPK inhibitor), indicating that the regulation of RAC1-MR signals by irisin depended on the activation of AMPK.Conclusions Irisin administration lowered salt-sensitive hypertension through regulating RAC1-MR signaling via activation of AMPK, which may be a promising therapeutic approach for salt-sensitive hypertension.

Single-cell RNA sequencing (scRNAseq) is a crucial tool in kidney research. These technologies cluster cells based on transcriptome similarity, irrespective of the anatomical location and order within the nephron. Thus, a transcriptome cluster may obscure the heterogeneity of the cell population within a nephron segment. Elevated dietary fructose leads to salt-sensitive hypertension, in part, through fructose reabsorption in the proximal tubule (PT). However, the organization of the four known fructose transporters in apical PTs (SGLT4, SGLT5, GLUT5, and NaGLT1) remains poorly understood. We hypothesized that cells within each subsegment of the proximal tubule exhibit complex, heterogeneous fructose transporter expression patterns. To test this hypothesis, we analyzed rat kidney transcriptomes and proteomes from publicly available scRNAseq and tubule microdissection databases. We found that microdissected PT-S1 segments consist of 81% ± 12% cells with scRNAseq-derived transcriptional characteristics of S1, whereas PT-S2 express a mixture of 18% ± 9% S1, 58% ± 8% S2, and 19% ± 5% S3 transcripts, and PT-S3 consists of 75% ± 9% S3 transcripts. The expression of all four fructose transporters was detectable in all three PT segments, but key fructose transporters SGLT5 and GLUT5 progressively increased from S1 to S3, and both were significantly upregulated in S3 vs. S1/S2 (Slc5a10: 1.9 log2FC, p < 1 × 10−299; Scl2a5: 1.4 log2FC, p < 4 × 10−105). A similar distribution was found in human kidneys. These data suggest that S3 is the primary site of fructose reabsorption in both humans and rats. Finally, because of the multiple scRNAseq transcriptional phenotypes found in each segment, our findings also imply that anatomical labels applied to scRNAseq clusters may be misleading. [ABSTRACT FROM AUTHOR]

Abstract Dahl salt‐sensitive (SS) rats fed a high‐salt diet, but not low‐salt, exhibit vascular dysfunction. Several substrains of SS rats exist that differ in their blood pressure phenotypes and salt sensitivity. The goal of this study was to investigate whether the John‐Rapp‐derived SS rat (SS/Jr), which exhibits spontaneous hypertension on a low‐salt diet, presents with hallmarks of vascular dysfunction observed in another experimental model of hypertension independent of dietary salt, the spontaneously hypertensive rat (SHR). Endothelium‐intact aortic rings and mesenteric resistance arteries were isolated from low‐salt fed adult male SS/Jr rats and SHRs, or their respective controls, for isometric wire myography. Vessels were challenged with cumulative concentrations of various vasoactive substances, in the absence or presence of nitric oxide synthase or cyclooxygenase inhibitors. Despite showing some differences in their responses to various vasoactive substances, both SS/Jr rats and SHRs exhibited key features of vascular dysfunction, including endothelial dysfunction and hyperresponsiveness to vasocontractile agonists. In conclusion, this study provides evidence to support the utility of the SS/Jr rat strain maintained on a low‐salt diet as a valid experimental model for vascular dysfunction, a key feature of human hypertension.

The endothelial glycocalyx is closely associated with various physiological and pathophysiological events. Significant modification of the endothelial glycocalyx is an early process in the pathogenesis of cardiovascular disease. High dietary salt and HIV infection damages the endothelial glycocalyx causing endothelial dysfunction and increasing the risk for salt-sensitive hypertension and cardiovascular disease. The two factors, HIV infection and dietary salt are critical independent predictors of hypertension and cardiovascular disease and often synergize to exacerbate and accelerate disease pathogenesis. Salt-sensitive hypertension is more common among people living with HIV and is associated with risk for cardiovascular disease, stroke, heart attack and even death. However, the underlying mechanisms linking endothelial glycocalyx damage to dietary salt and HIV infection are lacking. Yet, both HIV infection/treatment and dietary salt are closely linked to endothelial glycocalyx damage and development of salt-sensitive hypertension. Moreover, the majority of individuals globally, consume more salt than is recommended and the burden of HIV especially in sub-Sahara Africa is disproportionately high. In this review, we have discussed the missing link between high salt and endothelial glycocalyx shedding in the pathogenesis of salt-sensitive hypertension. We have further elaborated the role played by HIV infection and treatment in modifying endothelial glycocalyx integrity to contribute to the development of hypertension and cardiovascular disease.

In the current study, we took advantage of the loss of protection from hypertension in SSCD247-/- rats to characterize the pathological effects of renal T-cells in isolation from the confounding effects of elevated renal perfusion pressure. Male SSCD247-/- and SSCD247+/+ littermates were fed 4.0% NaCl (high salt) diet to induce hypertension. Blood pressure was assessed continuously throughout the time course with radiotelemetry. Urine albumin and protein excretion were assessed on the final day of high salt. Renal injury and medullary transcriptome were assessed after completion of the high salt protocol. In contrast to previous studies, mean arterial pressure was not significantly different between SSCD247-/- and SSCD247+/+ rats. Despite this lack of pressure difference, urinary albumin was significantly lower in SSCD247-/- rats than their wild-type littermates. In the outer medulla, substantially more transcriptomic changes were found to correlate with endpoint blood pressure than with the absence of presence of renal T-cells. We also demonstrated that renal histological damage was driven by elevated renal perfusion pressure rather than the presence of renal T-cells. In conclusion, using the loss of protection from hypertension in SSCD247-/- rats, we demonstrated that renal perfusion pressure has more profound pathological effects on the kidney than renal T-cells. However, renal T-cells, independently of blood pressure, modulate the progression of albuminuria. [ABSTRACT FROM AUTHOR]

Salt-sensitivity hypertension (SSHTN) is an independent predictor for cardiovascular mortality. VEGFC has been reported to be a protective role in SSHTN and hypertensive kidney injury. However, the underlying mechanisms remain largely unclear. The current study aimed to explore the protective effects and mechanisms of VEGFC against SSHTN and hypertensive nephropathy. Here, we reported that VEGFC attenuated high blood pressure as well as protected against renal inflammation and fibrosis in SSHTN mice. Moreover, VEGFC suppressed the activation of renal NLRP3 inflammasome in SSHTN mice. In vitro, we found VEGFC inhibited NLRP3 inflammasome activation, meanwhile, upregulated autophagy in high-salt-induced macrophages, while these effects were reversed by an autophagy inhibitor 3MA. Furthermore, in vivo, 3MA pretreatment weakened the protective effects of VEGFC on SSHTN and hypertensive nephropathy. Mechanistically, VEGF receptor 3 (VEGFR3) kinase domain activated AMPK by promoting the phosphorylation at Thr183 via binding to AMPK, thus enhancing autophagy activity in the context of high-salt-induced macrophages. These findings indicated that VEGFC inhibited NLRP3 inflammasome activation by promoting VEGFR3-AMPK-dependent autophagy pathway in high-salt-induced macrophages, which provided a mechanistic basis for the therapeutic target in SSHTN and hypertensive kidney injury. [ABSTRACT FROM AUTHOR]

Exercise training (Ex) has anti-hypertensive and renal protective effects. In this study, we investigate the effects of Ex on mitochondrial fatty acid metabolism in the kidneys of Dahl salt-sensitive (Dahl-S) rats fed a high-salt (HS) diet. Eight-week-old, male Dahl-S rats were divided into three groups: (1) normal-salt diet, sedentary (NS-Sed), (2) HS diet, sedentary (HS-Sed), and (3) HS-Ex. The NS and HS groups were fed a diet containing 0.6% and 8% NaCl, respectively. The HS-Ex group performed treadmill running for 8 weeks (5 days/week; 60 min/day at 16–20 m/min, 0% gradient). Renal function and the expression of enzymes and regulators of β-oxidation and electron transport chain (ETC) complexes were assessed. HS increased systolic blood pressure and proteinuria, and Ex ameliorated these defects. HS also reduced creatinine clearance, and Ex ameliorated it. HS reduced the renal expression of enzymes of β-oxidation (carnitine palmitoyltransferase type I (CPTI) and acyl-CoA dehydrogenases (CADs)) and the related transcription factors peroxisome proliferator-activated receptor α (PPARα) and PPARγ-coactivator-1α (PGC-1α), and Ex restored this. HS also reduced the renal expression of enzymes in ETC complexes, and Ex restored this expression. Ex ameliorates HS-induced renal damage by upregulating enzymes involved in fatty acid β-oxidation and ETC complexes via increases in PPAR-α and PGC-1α expressions in the kidneys of Dahl-S rats. These results suggest that Ex may have beneficial effects on HS-induced mitochondrial dysfunction in the kidney. [ABSTRACT FROM AUTHOR]

Purposeof Review: Female sex hormones have systemic effects unrelated to their reproductive function. We describe experiences of different research groups and our own, on aspects related to the importance of female sex hormones on blood pressure (BP) regulation and salt-sensitivity-mediated BP response and salt sensitivity without alterations in BP, as well as renal sodium handling and interactions with the immune system. Recent Findings: Changes in sodium intake in normotensive premenopausal women cause more BP variations than in men. After menopause, women often develop arterial hypertension (HT) with a profile of sodium sensitivity. Besides, experimental results have shown that in adult rat models resembling the postmenopausal hormonal state induced by ovariectomy, controlling BP is not enough to avoid renal and other tissue infiltration with immune cells, which does not occur when sodium intake is low or normal. Therefore, excess sodium promotes an inflammatory state with the involvement of immune cells. The evidence of activation of adaptive immunity, besides changes in T cell subpopulations, includes changes in sodium transporters and receptors. Summary: More studies are needed to evaluate the particular sodium sensitivity of women and its meaning. Changes in lifestyle and sodium intake reduction are the main therapeutic steps. However, to face the actual burden of salt-sensitive HT in postmenopausal women and its associated inflammatory/immune changes, it seems reasonable to work on immune cell activity by considering the peripheral blood mononuclear cell phenotypes of molecules and transport proteins related to sodium handle, both to screen for and treat cell activation. [ABSTRACT FROM AUTHOR]

Background Klotho is closely related to the occurrence and development of kidney disease. Salt-sensitive hypertension (SSH) is often accompanied by kidney disease. At present, there are few reports on the role and molecules mechanism of klotho in renal injury in SSH. Objective To investigate the role and molecules mechanism of klotho in renal injury in SSH. Methods The rat glomerular mesangial cell line HBZY1 was selected as the experimental cells from June 2021 to January 2022, and the experimental cells were divided into the control group and the model group. The model of HBZY1 cell injury induced by NaCl 137 mmol/L and angiotensin Ⅱ (Ang Ⅱ) 10-6 mmol/L was used to simulate the renal injury in SSH, and the cells were collected. The differences in the expression of klotho mRNA and protein were detected by real-time fluorescent quantitative PCR (qRT-PCR) and Western Blot. The interference vector and overexpression vector of klotho and the overexpression vector of angiotensin Ⅱ type 1 receptor (AT1R) were constructed. The klotho interference experiments were divided into five groups, including the control group, empty group, klotho-siRNA1 group, klotho-siRNA2 group and klotho-siRNA3 group; the klotho overexpression experiments were divided into three groups, including the control group, empty group and klotho overexpression group; the AT1R overexpression experiments were divided into three groups, including the control group, empty group and AT1R overexpression group. The constructed vectors were transfected into cells with verified transfection efficiency. After successful transfection, the experiment was divided into two parts. The first part of the experiment was to verify the renal protective effect of klotho, the experiment subjects were divided into four groups, including the control group, model group, klotho overexpression group and klotho interference group. The second part of the experiment was to explore whether the renal protective effect of klotho was related to AT1R, the experiment subjects were divided into three groups, including the model group, klotho overexpression group and klotho+AT1R overexpression group. After successful transfection, the tests including cell viability detected by cell counting kit-8 (CCK-8) method, reactive oxygen species (ROS) content detected by flow cytometry, malondialdehyde (MDA) and superoxide dismutase (SOD) content in cell supernatant detected by enzyme-linked immunosorbent assay (ELISA) , interaction effect between kltho and AT1R detected by co-immunoprecipitation (Co-IP) . Results Compared with the control group, mRNA level and protein expression of klotho in the model group decreased in model group (t=7.102, 7.506; P=0.002, 0.002) , klotho-siRNA2 interference effect was more significant (P

Heart failure (HF) preserved ejection fraction (HFpEF) accounts for almost 50% of HF, and hypertension is one of the pathogenies. The MAPK signaling pathway is closely linked to heart failure and hypertension; however, its function in HEpEF resulting from salt-sensitive hypertension is not well understood. In this work, a salt-sensitive hypertension-induced HEpEF model was established based on deoxycorticosterone acetate-salt (DOCA-salt) hypertension mice. The impact of the MAPK inhibitor (Doramapimod) on HEpEF induced by salt-sensitive hypertension was assessed through various measures, such as blood pressure, transthoracic echocardiography, running distance, and histological analysis, to determine its therapeutic effectiveness on cardiac function. In addition, the effects of high salt on myogenic cells were also evaluated in vitro using qRTPCR. The LV ejection fractions (LVEF) in DOCA-salt hypertension mice were over 50%, indicating that the salt-sensitive hypertension-induced HFpEF model was successful. RNA-seq revealed that the MAPK signaling pathway was upregulated in the HFpEF model compared with the normal mice, accompanied by hypertension, impaired running distance, restricted cardiac function, increased cross-sectional and fibrosis area, and upregulation of heart failure biomarkers, including GAL-3, LDHA and BNP. The application of Doramapimod could improve blood pressure, cardiomyocyte hypertrophy, and myocardial fibrosis, as well as decrease the aforementioned heart failure biomarkers. The qRTPCR results showed similar findings to these observations. Our findings suggest that the use of a MAPK inhibitor (Doramapimod) could be a potential treatment for salt-sensitive hypertension-induced HFpEF.

Single-cell RNA sequencing (scRNAseq) is a crucial tool in kidney research. These technologies cluster cells based on transcriptome similarity, irrespective of the anatomical location and order within the nephron. Thus, a transcriptome cluster may obscure the heterogeneity of the cell population within a nephron segment. Elevated dietary fructose leads to salt-sensitive hypertension, in part, through fructose reabsorption in the proximal tubule (PT). However, the organization of the four known fructose transporters in apical PTs (SGLT4, SGLT5, GLUT5, and NaGLT1) remains poorly understood. We hypothesized that cells within each subsegment of the proximal tubule exhibit complex, heterogeneous fructose transporter expression patterns. To test this hypothesis, we analyzed rat kidney transcriptomes and proteomes from publicly available scRNAseq and tubule microdissection databases. We found that microdissected PT-S1 segments consist of 81% ± 12% cells with scRNAseq-derived transcriptional characteristics of S1, whereas PT-S2 express a mixture of 18% ± 9% S1, 58% ± 8% S2, and 19% ± 5% S3 transcripts, and PT-S3 consists of 75% ± 9% S3 transcripts. The expression of all four fructose transporters was detectable in all three PT segments, but key fructose transporters SGLT5 and GLUT5 progressively increased from S1 to S3, and both were significantly upregulated in S3 vs. S1/S2 (Slc5a10: 1.9 log2FC, p < 1 × 10−299; Scl2a5: 1.4 log2FC, p < 4 × 10−105). A similar distribution was found in human kidneys. These data suggest that S3 is the primary site of fructose reabsorption in both humans and rats. Finally, because of the multiple scRNAseq transcriptional phenotypes found in each segment, our findings also imply that anatomical labels applied to scRNAseq clusters may be misleading.

BackgroundCardiovascular diseases persist as the primary cause of mortality in the global population. Hypertension (HTN) is widely recognized as one of the most crucial risk factors contributing to severe cardiovascular conditions. In recent years, a growing body of research has highlighted the therapeutic potential of gut microbiota (GM) in addressing cardiovascular diseases, particularly HTN. Consequently, unraveling and synthesizing the connections between GM and HTN, key research domains, and the underlying interaction mechanisms have grown increasingly vital.MethodsWe retrieved articles related to GM and HTN from 2014 to 2023 using Web of Science. Bibliometric tools employed in this analysis include CiteSpace and VOSviewer.ResultFrom 2014 to 2023, we identified 1,730 related articles. These articles involved 88 countries (regions) and 9,573 authors. The articles were published in 593 journals, with 1000 references exhibiting co-occurrence more than 10 times. The number of studies in this field has been increasing, indicating that it remains a research hotspot. We expect this field to continue gaining attention in the future. China leads in the number of published articles, while the United States boasts the most extensive international collaborations, signifying its continued prominence as a research hub in this domain. Tain You-Lin, Hsu Chien-Ning, Raizada Mohan K, and Yang Tao are among the authors with the highest publication volume. Publications in this field are frequently found in nutrition, cardiovascular, and molecular biology journals. The most frequently occurring keywords include metabolic syndrome, cardiovascular disease, inflammation, short-chain fatty acids, trimethylamine N-oxide, chronic kidney disease, heart failure, and high-salt diet.ConclusionThe relationship between GM and HTN is presently one of the most active research areas. By employing bibliometric tools, we analyzed critical and innovative articles in this field to provide an objective summary of the primary research directions, such as the relationship between GM and HTN, GM metabolites, high-salt diet, the developmental origins of health and disease, obstructive sleep apnea-Induced hypertension and antihypertensive peptide. Our analysis aims to offer researchers insights into hotspots and emerging trends in the field of GM and HTN for future research reference.

Preventing hypertension by restricting dietary salt intake, sodium chloride, is well established in public health policy, but a pathophysiological mechanism has yet to explain the controversial clinical finding that some individuals have a greater risk of hypertension from exposure to salt intake, termed salt-sensitive hypertension. The present perspective paper synthesizes interdisciplinary findings from the research literature and offers novel insights proposing that the pathogenesis of salt-sensitive hypertension is mediated by interaction of salt-induced hypervolemia and phosphate-induced vascular calcification. Arterial stiffness and blood pressure increase as calcification in the vascular media layer reduces arterial elasticity, preventing arteries from expanding to accommodate extracellular fluid overload in hypervolemia related to salt intake. Furthermore, phosphate has been found to be a direct inducer of vascular calcification. Reduction of dietary phosphate may help reduce salt-sensitive hypertension by lowering the prevalence and progression of vascular calcification. Further research should investigate the correlation of vascular calcification with salt-sensitive hypertension, and public health recommendations to prevent hypertension should encourage reductions of both sodium-induced hypervolemia and phosphate-induced vascular calcification. [ABSTRACT FROM AUTHOR]

Through its classic ATP‐dependent ion‐pumping function, basolateral Na/K‐ATPase (NKA) generates the Na+ gradient that drives apical Na+ reabsorption in the renal proximal tubule (RPT), primarily through the Na+/H+ exchanger (NHE3). Accordingly, activation of NKA‐mediated ion transport decreases natriuresis through activation of basolateral (NKA) and apical (NHE3) Na+ reabsorption. In contrast, activation of the more recently discovered NKA signaling function triggers cellular redistribution of RPT NKA and NHE3 and decreases Na+ reabsorption. We used gene targeting to test the respective contributions of NKA signaling and ion pumping to the overall regulation of RPT Na+ reabsorption. Knockdown of RPT NKA in cells and mice increased membrane NHE3 and Na+/HCO3− cotransporter (NBCe1A). Urine output and absolute Na+ excretion decreased by 65%, driven by increased RPT Na+ reabsorption (as indicated by decreased lithium clearance and unchanged glomerular filtration rate), and accompanied by elevated blood pressure. This hyper reabsorptive phenotype was rescued upon crossing with RPT NHE3−/− mice, confirming the importance of NKA/NHE3 coupling. Hence, NKA signaling exerts a tonic inhibition on Na+ reabsorption by regulating key apical and basolateral Na+ transporters. This action, lifted upon NKA genetic suppression, tonically counteracts NKA's ATP‐driven function of basolateral Na+ reabsorption. Strikingly, NKA signaling is not only physiologically relevant but it also appears to be functionally dominant over NKA ion pumping in the control of RPT reabsorption. [ABSTRACT FROM AUTHOR]

Endothelin-1 (ET-1) is a peptide hormone that acts on its receptors to regulate sodium handling in the kidney's collecting duct. Dysregulation of the endothelin axis is associated with various diseases, including salt-sensitive hypertension and chronic kidney disease. Previously, our lab has shown that the circadian clock gene PER1 regulates ET-1 levels in mice. However, the regulation of ET-1 by PER1 has never been investigated in rats. Therefore, we used a novel model where knockout of Per1 was performed in Dahl salt-sensitive rat background (SSPer1−/−) to test a hypothesis that PER1 regulates the ET-1 axis in this model. Here, we show increased renal ET-1 peptide levels and altered endothelin axis gene expression in several tissues, including the kidney, adrenal glands, and liver in SSPer1−/− compared with control SS rats. Edn1 antisense lncRNA Edn1-AS, which has previously been suggested to be regulated by PER1, was also altered in SSPer1−/− rats compared with control SS rats. These data further support the hypothesis that PER1 is a negative regulator of Edn1 and is important in the regulation of the endothelin axis in a tissue-specific manner. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is a common clinical disease with an increasing incidence, affecting 10 to 15% of the world's population. Hypertension is the most common and modifiable risk factor for preventing adverse cardiovascular outcomes in patients with CKD. A survey from developed countries shows that 47% of hypertensive patients over the age of 20 have uncontrolled blood pressure (BP), and the control rate is even lower in developing countries. CKD is both a common cause of uncontrolled hypertension and a risk factor for altered sequelae. In particular, studies have demonstrated that abnormal blood-pressure patterns in CKD patients, such as non-dipping-blood-pressure patterns, are associated with a significantly increased risk of cardiovascular (CV) disease. The distal convoluted tubule (DCT) is a region of the kidney, and although only 5–10% of the sodium (Na+) filtered by the glomerulus is reabsorbed by DCT, most studies agree that Na-Cl cotransporter (NCC) in human, rabbit, mouse, and rat kidneys is the most important route of sodium reabsorption across the DCT for maintaining the homeostasis of sodium. The regulation of NCC involves a large and complex network structure, including certain physiological factors, kinases, scaffold proteins, transporter phosphorylation, and other aspects. This regulation network includes various levels. Naturally, cross-talk between the components of this system must occur in order to relay the important signals to the transporter to play its role. Knowledge of the mechanisms regulating NCC activation is critical for understanding and treating hypertension and CKD. Previous studies from our laboratory have investigated the mechanisms through which NCC is activated in several different models. In the following sections, we review the literature on the mechanisms of NCC in relation to hypertension in CKD. [ABSTRACT FROM AUTHOR]

Salt-sensitive hypertension is closely related to inflammation, but the mechanism is barely known. Transmembrane member 16A (TMEM16A) is the Ca2+-activated chloride channel in epithelial cells, smooth muscle cells, and sensory neurons. It can promote inflammatory responses by increasing proinflammatory cytokine release. Here, we identified a positive role of TMEM16A in vascular inflammation. The expression of TMEM16A was increased in high-salt-stimulated vascular smooth muscle cells (VSMCs), whereas inhibiting TMEM16A or silencing TMEM16A with small interfering RNA (siRNA) can abolish this effect in vitro or in vivo. Transcriptome analysis of VSMCs revealed some differential downstream genes of TMEM16A related to inflammation, such as endothelial cell-specific molecule 1 (ESM1) and CXC chemokine ligand 16 (CXCL16). Overexpression of TMEM16A in VSMCs was accompanied by high levels of ESM1, CXCL16, intercellular adhesion molecule-1 (ICAM-1), and vascular adhesion molecule-1 (VCAM-1). We treated VSMCs cultured with high salt and arctigenin (ARC), T16Ainh-A01 (T16), and TMEM16A siRNA (siTMEM16A), leading to greatly decreased ESM1, CXCL16, VCAM-1, and ICAM-1. Beyond that, silencing ESM1, the expression of VCAM-1 and ICAM-1, and CXCL16 was attenuated. In conclusion, our results outlined a signaling scheme that increased TMEM16 protein upregulated ESM1, which possibly activated the CXCL16 pathway and increased VCAM-1 and ICAM-1 expression, which drives VSMC inflammation. Beyond that, arctigenin, as a natural inhibitor of TMEM16A, can reduce the systolic blood pressure (SBP) of salt-sensitive hypertension mice and alleviate vascular inflammation. [ABSTRACT FROM AUTHOR]

Salt-induced renal metabolism dysfunction is an important mechanism of salt-sensitive hypertension. Given that the gut-liver axis is the first hit of a high-salt diet (HSD), we aimed to identify the extra-renal mechanism from hepatic metabolism and gut microbiota, and attempted to relieve the salt-induced metabolic dysfunctions by curcumin. Untargeted metabolomics analysis was performed to identify the changes in hepatic metabolic pathways, and integrated analysis was employed to reveal the relationship between hepatic metabolic dysfunction and gut microbial composition. HSD induced significant increase in fumaric acid, l-lactic acid, creatinine, l-alanine, glycine, and l-cysteine levels, and amino acids metabolism pathways associated with glycolysis were significantly altered, including alanine, aspartate, and glutamate metabolism; glycine, serine, and threonine metabolism, which were involved in the regulation of blood pressure. Integrated multi-omics analysis revealed that changes in Paraprevotella, Erysipelotrichaceae, and genera from Clostridiales are associated with metabolic disorders. Gene functional predication analysis based on 16S Ribosomal RNA sequences showed that the dysfunction in hepatic metabolism were correlated with enhanced lipopolysaccharide (LPS) biosynthesis and apoptosis in gut microbes. Curcumin (50 mg/kg/d) might reduce gut microbes-associated LPS biosynthesis and apoptosis, partially reverse metabolic dysfunction, ameliorate renal oxidative stress, and protect against salt-sensitive hypertension. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is the fourth most deadly cancer globally. The adducin 1 (ADD1) protein is involved in oncogenic signal transduction pathways in several types of cancer, and the rs4961 variant (c.1378 G>T, p.Gly460Trp) of the ADD1 gene is associated with salt-sensitive hypertension, renal cell cancer and breast cancer susceptibility; however, it has not been investigated in GC. The aim of the present study was to evaluate the association between the rs4961 variant and the development of GC and preneoplastic gastric lesions (PGLs) in a population from western Mexico. A total of 225 individuals who underwent an endoscopy were evaluated, of which 71 patients had histopathologically diagnosed GC and 53 patients had PGLs, with 101 patients used as controls. The rs4961 variant was genotyped by using PCR and DNA sequencing. The frequency of the mutated homozygous genotype (TT) of the rs4961 variant was <10% in the three evaluated groups, and the frequency of the minor allele (T) was <21% in the GC, PGL and control groups. Genotypic and allelic frequencies were similarly distributed in all of the studied groups (P>0.05). In summary, in the study population, the rs4961 variant was not associated with GC risk; however, its role in other populations and in other types of cancer is worthy of future research. [ABSTRACT FROM AUTHOR]

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. • Hypertension is accompanied by changes in the expression and activity of proteins in peripheral blood mononuclear cells. • High salt, but not high blood pressure, induces immune cell activation and renal infiltration. • The presence or absence of female sex hormones is a determining factor in the changes observed in Na+ K+- ATPase in response to high sodium intake. [ABSTRACT FROM AUTHOR]

Exercise training (Ex) has anti-hypertensive and renal protective effects. In this study, we investigate the effects of Ex on mitochondrial fatty acid metabolism in the kidneys of Dahl salt-sensitive (Dahl-S) rats fed a high-salt (HS) diet. Eight-week-old, male Dahl-S rats were divided into three groups: (1) normal-salt diet, sedentary (NS-Sed), (2) HS diet, sedentary (HS-Sed), and (3) HS-Ex. The NS and HS groups were fed a diet containing 0.6% and 8% NaCl, respectively. The HS-Ex group performed treadmill running for 8 weeks (5 days/week; 60 min/day at 16–20 m/min, 0% gradient). Renal function and the expression of enzymes and regulators of β-oxidation and electron transport chain (ETC) complexes were assessed. HS increased systolic blood pressure and proteinuria, and Ex ameliorated these defects. HS also reduced creatinine clearance, and Ex ameliorated it. HS reduced the renal expression of enzymes of β-oxidation (carnitine palmitoyltransferase type I (CPTI) and acyl-CoA dehydrogenases (CADs)) and the related transcription factors peroxisome proliferator-activated receptor α (PPARα) and PPARγ-coactivator-1α (PGC-1α), and Ex restored this. HS also reduced the renal expression of enzymes in ETC complexes, and Ex restored this expression. Ex ameliorates HS-induced renal damage by upregulating enzymes involved in fatty acid β-oxidation and ETC complexes via increases in PPAR-α and PGC-1α expressions in the kidneys of Dahl-S rats. These results suggest that Ex may have beneficial effects on HS-induced mitochondrial dysfunction in the kidney.

Proximal tubule fructose metabolism is key to fructose‐induced hypertension, but the roles of sex and stress are unclear. We hypothesized that females are resistant to the salt‐sensitive hypertension caused by low amounts of dietary fructose compared to males and that the magnitude of the increase in blood pressure (BP) depends, in part, on amplification of the stress response of renal sympathetic nerves. We measured systolic BP (SBP) in rats fed high salt with either no sugar (HS), 20% glucose (GHS) or 20% fructose (FHS) in the drinking water for 7–8 days. FHS increased SBP in both males (Δ22 ± 9 mmHg; p < 0.046) and females (Δ16 ± 3 mmHg; p < 0.0007), while neither GHS nor HS alone induced changes in SBP in either sex. The FHS‐induced increase in SBP as measured by telemetry in the absence of added stress (8 ± 2 mmHg) was significantly lower than that measured by plethysmography (24 ± 5 mmHg) (p < 0.014). However, when BP was measured by telemetry simulating the stress of plethysmography, the increase in SBP was significantly greater (15 ± 3 mmHg) than under low stress (8 ± 1 mmHg) (p < 0.014). Moderate‐stress also increased telemetric diastolic (p < 0.006) and mean BP (p < 0.006) compared to low‐stress in FHS‐fed animals. Norepinephrine excretion was greater in FHS‐fed rats than HS‐fed animals (Male: 6.4 ± 1.7 vs.1.8 ± 0.4 nmole/kg/day; p < 0.02. Female 54 ± 18 vs. 1.2 ± 0.6; p < 0.02). We conclude that fructose‐induced salt‐sensitive hypertension is similar in males and females unlike other forms of hypertension, and the increase in blood pressure depends in part on an augmented response of the sympathetic nervous system to stress. [ABSTRACT FROM AUTHOR]

Atrial natriuretic peptide (ANP)-mediated natriuresis is known as a cardiac endocrine function in sodium and body fluid homeostasis. Corin is a protease essential for ANP activation. Here, we studied the role of renal corin in regulating salt excretion and blood pressure. We created corin conditional knockout (cKO), in which the Corin gene was selectively disrupted in the kidney (kcKO) or heart (hcKO). We examined the blood pressure, urinary Na+ and Cl− excretion, and cardiac hypertrophy in wild-type, corin global KO, kcKO, and hcKO mice fed normal- and high-salt diets. We found that on a normal-salt diet (0.3% NaCl), corin kcKO and hcKO mice had increased blood pressure, indicating that both renal and cardiac corin is necessary for normal blood pressure in mice. On a high-salt diet (4% NaCl), reduced urinary Na+ and Cl− excretion, increased body weight, salt-exacerbated hypertension, and cardiac hypertrophy were observed in corin kcKO mice. In contrast, impaired urinary Na+ and Cl− excretion and salt-exacerbated hypertension were not observed in corin hcKO mice. These results indicated that renal corin function is important in enhancing natriuresis upon high salt intakes and that this function cannot be compensated by the cardiac corin function in mice. [ABSTRACT FROM AUTHOR]

Most hypertensive cases are primary and heavily associated with modifiable risk factors like salt intake. Evidence suggests that even small reductions in salt consumption reduce blood pressure in all age groups. In that regard, the ACC/AHA described a distinct set of individuals who exhibit salt-sensitivity, regardless of their hypertensive status. Data has shown that salt-sensitivity is an independent risk factor for cardiovascular events and mortality. However, despite extensive research, the pathogenesis of salt-sensitive hypertension is still unclear and tremendously challenged by its multifactorial etiology, complicated genetic influences, and the unavailability of a diagnostic tool. So far, the important roles of the renin-angiotensin-aldosterone system, sympathetic nervous system, and immune system in the pathogenesis of salt-sensitive hypertension have been studied. In the first part of this review, we focus on how the systems mentioned above are aberrantly regulated in salt-sensitive hypertension. We follow this with an emphasis on genetic variants in those systems that are associated with and/or increase predisposition to salt-sensitivity in humans. [ABSTRACT FROM AUTHOR]

The brain renin-angiotensin system plays important roles in blood pressure and cardiovascular regulation. There are two isoforms of prorenin in the brain: the classic secreted form (prorenin/sREN) encoded by renin-a, and an intracellular form (icREN) encoded by renin-b. Emerging evidence indicates the importance of renin-b in cardiovascular and metabolic regulation. However, the role of endogenous brain prorenin in the development of salt-sensitive hypertension remains undefined. In this study, we test the hypothesis that renin-a produced locally in the brain contributes to the pathogenesis of hypertension. Using RNAscope, we report for the first time that renin mRNA is expressed in several regions of the brain, including the subfornical organ (SFO), the paraventricular nucleus of the hypothalamus (PVN), and the brainstem, where it is found in glutamatergic, GABAergic, cholinergic, and tyrosine hydroxylase-positive neurons. Notably, we found that renin mRNA was significantly elevated in the SFO and PVN in a mouse model of DOCA-salt–induced hypertension. To examine the functional importance of renin-a in the SFO, we selectively ablated renin-a in the SFO in renin-a–floxed mice using a Cre-lox strategy. Importantly, renin-a ablation in the SFO attenuated the maintenance of DOCA-salt–induced hypertension and improved autonomic function without affecting fluid or sodium intake. Molecularly, ablation of renin-a prevented the DOCA-salt–induced elevation in NADPH oxidase 2 (NOX2) in the SFO without affecting NOX4 or angiotensin II type 1 and 2 receptors. Collectively, our findings demonstrate that endogenous renin-a within the SFO is important for the pathogenesis of salt-sensitive hypertension. [ABSTRACT FROM AUTHOR]

Dietary salt intake is a long-debated issue. Increased sodium intake is associated with high blood pressure, leading to salt-sensitive hypertension. Excessive salt intake leads to arterial stiffness in susceptible individuals via impaired nitric oxide action and increased endothelin-1 expression, overactivity of the renal sympathetic nervous system and also via aldosterone-independent activation of the mineralocorticoid receptor. Salt restriction in such individuals reduces blood pressure (BP) values. The optimal level of salt restriction that leads to improved cardiovascular outcomes is still under debate. Current BP and dietary guidelines recommend low sodium intake for the general population. However, a specific category of patients does not develop arterial hypertension in response to sodium loading. In addition, recent research demonstrates the deleterious effects of aggressive sodium restriction, even in heart failure patients. This mini review discusses current literature data regarding the advantages and disadvantages of salt restriction and how it impacts the overall health status. [ABSTRACT FROM AUTHOR]

Background: The nonsteroidal mineralocorticoid receptor blocker esaxerenone is effective in reducing blood pressure (BP). Objective: In this study, we investigated esaxerenone-driven sodium homeostasis and its association with changes in BP in Dahl salt-sensitive (DSS) hypertensive rats. Methods: In the different experimental setups, we evaluated BP by a radiotelemetry system, and sodium homeostasis was determined by an approach of sodium intake (food intake) and excretion (urinary excretion) in DSS rats with a low-salt diet (0.3% NaCl), high-salt diet (HSD, 8% NaCl), HSD plus 0.001% esaxerenone (w/w), and HSD plus 0.05% furosemide. Results: HSD-fed DSS rats showed a dramatic increase in BP with a non-dipper pattern, while esaxerenone treatment, but not furosemide, significantly reduced BP with a dipper pattern. The cumulative sodium excretion in the active period was significantly elevated in esaxerenone- and furosemide-treated rats compared with their HSD-fed counterparts. Sodium content in the skin, skinned carcass, and total body tended to be lower in esaxerenone-treated rats than in their HSD-fed counterparts, while these values were unchanged in furosemide-treated rats. Consistently, sodium balance tended to be reduced in esaxerenone-treated rats during the active period. Histological evaluation showed that esaxerenone, but not furosemide, treatment attenuated glomerulosclerosis, tubulointerstitial fibrosis, and urinary protein excretion induced by high salt loading. Conclusions: Collectively, these findings suggest that an esaxerenone treatment-induced reduction in BP and renoprotection are associated with body sodium homeostasis in salt-loaded DSS rats. [ABSTRACT FROM AUTHOR]

The essential role of the inwardly rectifying potassium channel K ir 5.1 (KCNJ16) in controlling electrolyte homeostasis and blood pressure has been demonstrated in human and animal studies. Previous studies have identified several bi-allelic mutations of KCNJ16 in humans, causing severe hypokalemia, renal salt wasting, and disturbed acid-base homeostasis. Here, we identified a novel homozygous variant of KCNJ16, I26T, in an Amish patient affected with polydipsia, developmental delay, and chronic metabolic acidosis with low serum bicarbonate concentration. Subsequently, we generated the rat model with I26T mutation using Dahl salt-sensitive rat (I26T rat) to characterize this variant. The male mutant rats displayed similar blood pressure and electrolyte homeostasis under baseline and with a high salt (4% NaCl) challenge. Blood pH, HCO 3 - and renal damage also remained similar between WT and I26T rats after high salt challenge. Additionally, single-channel patch clamp analysis revealed similar channel activity in CHO cells overexpressed with WT and I26T mutant K ir 4.1/5.1 channels. In summary, this study reported a novel variant in KCNJ16, namely I26T, which is likely a benign variant and not associated with pathologic phenotype in either human or Dahl salt-sensitive rats, indicating that the type/location of variant should be considered when diagnosing and treating patients with KCNJ16 mutations., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Abstract Proximal tubule fructose metabolism is key to fructose‐induced hypertension, but the roles of sex and stress are unclear. We hypothesized that females are resistant to the salt‐sensitive hypertension caused by low amounts of dietary fructose compared to males and that the magnitude of the increase in blood pressure (BP) depends, in part, on amplification of the stress response of renal sympathetic nerves. We measured systolic BP (SBP) in rats fed high salt with either no sugar (HS), 20% glucose (GHS) or 20% fructose (FHS) in the drinking water for 7–8 days. FHS increased SBP in both males (Δ22 ± 9 mmHg; p

Most hypertensive cases are primary and heavily associated with modifiable risk factors like salt intake. Evidence suggests that even small reductions in salt consumption reduce blood pressure in all age groups. In that regard, the ACC/AHA described a distinct set of individuals who exhibit salt-sensitivity, regardless of their hypertensive status. Data has shown that salt-sensitivity is an independent risk factor for cardiovascular events and mortality. However, despite extensive research, the pathogenesis of salt-sensitive hypertension is still unclear and tremendously challenged by its multifactorial etiology, complicated genetic influences, and the unavailability of a diagnostic tool. So far, the important roles of the renin-angiotensin-aldosterone system, sympathetic nervous system, and immune system in the pathogenesis of salt-sensitive hypertension have been studied. In the first part of this review, we focus on how the systems mentioned above are aberrantly regulated in salt-sensitive hypertension. We follow this with an emphasis on genetic variants in those systems that are associated with and/or increase predisposition to salt-sensitivity in humans.

Background Salt‐sensitive hypertension is highly prevalent and associated with cardiorenal damage. Large clinical trials have demonstrated that SGLT2 (sodium‐glucose cotransporter 2) inhibitors exert hypotensive effect and cardiorenal protective benefits in patients with hypertension with and without diabetes. However, the underlying mechanism remains elusive. Methods and Results Dahl salt‐sensitive rats and salt‐insensitive controls were fed with 8% high‐salt diet and some of them were treated with canagliflozin. The blood pressure, urinary sodium excretion, and vascular function were detected. Transient receptor potential channel 3 (TRPC3) knockout mice were used to explain the mechanism. Canagliflozin treatment significantly reduced high‐salt‐induced hypertension and this effect was not totally dependent on urinary sodium excretion in salt‐sensitive hypertensive rats. Assay of vascular function and proteomics showed that canagliflozin significantly inhibited vascular cytoplasmic calcium increase and vasoconstriction in response to high‐salt diet. High salt intake increased vascular expression of TRPC3 in salt‐sensitive rats, which could be alleviated by canagliflozin treatment. Overexpression of TRPC3 mimicked salt‐induced vascular cytosolic calcium increase in vitro and knockout of TRPC3 erased the antihypertensive effect of canagliflozin. Mechanistically, high‐salt‐induced activation of NCX1 (sodium‐calcium exchanger 1) reverse mode increased cytoplasmic calcium level and vasoconstriction, which required TRPC3, and this process could be blocked by canagliflozin. Conclusions We define a previously unrecognized role of TRPC3/NCX1 mediated vascular calcium dysfunction in the development of high‐salt‐induced hypertension, which can be improved by canagliflozin treatment. This pathway is potentially a novel therapeutic target to antagonize salt‐sensitive hypertension.

BackgroundSalt-sensitive hypertension (SSH) is a common type of essential hypertension in China. In recent years, although an increasing number of researches have focused on SSH, few studies have been researched on patients with SSH. The objective of this study was to explore the genes and pathways linked with SSH using RNA-sequencing (RNA-seq).Materials and methodsWe used RNA-seq to analyze the transcriptome of peripheral blood mononuclear cells (PBMCs) of five SSH patients and five SRH patients. Next, we analyzed the differentially expressed genes (DEGs) using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and Gene Set Enrichment (GSEA) enrichment analysis. Then, Cytoscape was used to construct the protein-protein interaction (PPI) network and the hub genes. Finally, CMAP analysis found that several small molecular compounds could reverse the altered DEGs.ResultsA total of 431 DEGs were found in the PBMC samples, including 294 up-regulated and 137 down-regulated genes. Functional enrichment analysis found significant enrichment in immune-related associations such as inflammation, chemokine, and cytokine-cytokine receptor interaction. The hub genes of the two modules were IL-6, IL-1A, CCL2, CCL3L3, and BUB1. In addition, we identified two small molecular compounds (iopromide and iloprost) that potentially interacted with DEGs.ConclusionThis study suggests some potential biomarkers for the diagnosis of SSH. It provides new insights into SSH diagnosis and possible future clinical treatment.

The ischemia–reperfusion injury (IRI) of rat kidneys is used as a model of acute kidney injury. Salt-sensitive hypertension occurs in rats after IRI, and the distal nephrons play important roles in the development of this condition. We investigated the role of the mineralocorticoid receptor (MR) in the progression of IRI-induced salt-sensitive hypertension in rats. Fourteen days after right-side nephrectomy, IRI was induced by clamping the left renal artery, with sham surgery performed as a control. IRI rats were provided with normal water or water with 1.0% NaCl (IRI/NaCl), or they were implanted with an osmotic mini-pump to infuse vehicle or aldosterone (IRI/Aldo). Esaxerenone, a non-steroidal MR blocker (MRB), was administered to IRI/NaCl and IRI/Aldo rats for 6 weeks. MR expression increased by day 7 post-IRI. Blood pressure and urinary protein excretion increased in IRI/NaCl and IRI/Aldo rats over the 6-week period, but these effects were negated by MRB administration. The MRB attenuated the expression of the gamma-epithelial sodium channel (ENaC) and renal damage. The ENaC inhibitor, amiloride, ameliorated hypertension and renal damage in IRI/NaCl and IRI/Aldo rats. Our findings thus showed that MR upregulation may play a pivotal role in ENaC-mediated sodium uptake in rats after IRI, resulting in the development of salt-sensitive hypertension in response to salt overload or the activation of the renin–angiotensin–aldosterone system. [ABSTRACT FROM AUTHOR]