-
Hypertension (Dallas, Tex. : 1979) Mar 2024Salt (sodium chloride) is an essential nutrient required to maintain physiological functions. However, for most people, daily salt intake far exceeds their physiological... (Review)
Review
Salt (sodium chloride) is an essential nutrient required to maintain physiological functions. However, for most people, daily salt intake far exceeds their physiological need and is habitually greater than recommended upper thresholds. Excess salt intake leads to elevation in blood pressure which drives cardiovascular morbidity and mortality. Indeed, excessive salt intake is estimated to be responsible for ≈5 million deaths per year globally. For approximately one-third of otherwise healthy individuals (and >50% of those with hypertension), the effect of salt intake on blood pressure elevation is exaggerated; such people are categorized as salt sensitive and salt sensitivity of blood pressure is considered an independent risk factor for cardiovascular disease and death. The prevalence of salt sensitivity is higher in women than in men and, in both, increases with age. This narrative review considers the foundational concepts of salt sensitivity and the underlying effector systems that cause salt sensitivity. We also consider recent updates in preclinical and clinical research that are revealing new modifying factors that determine the blood pressure response to high salt intake.
Topics: Male; Humans; Female; Sodium Chloride, Dietary; Sodium Chloride; Hypertension; Cardiovascular Diseases; Blood Pressure
PubMed: 37721034
DOI: 10.1161/HYPERTENSIONAHA.123.17959 -
Journal of Pharmaceutical Analysis Dec 2023The () of cation-chloride cotransporters (CCCs) comprises potassium chloride cotransporters (KCCs, e.g. KCC1, KCC2, KCC3, and KCC4)-mediated Cl extrusion, and sodium... (Review)
Review
The () of cation-chloride cotransporters (CCCs) comprises potassium chloride cotransporters (KCCs, e.g. KCC1, KCC2, KCC3, and KCC4)-mediated Cl extrusion, and sodium potassium chloride cotransporters (N[K]CCs, NKCC1, NKCC2, and NCC)-mediated Cl loading. The CCCs play vital roles in cell volume regulation and ion homeostasis. Gain-of-function or loss-of-function of these ion transporters can cause diseases in many tissues. In recent years, there have been considerable advances in our understanding of CCCs' control mechanisms in cell volume regulations, with many techniques developed in studying the functions and activities of CCCs. Classic approaches to directly measure CCC activity involve assays that measure the transport of potassium substitutes through the CCCs. These techniques include the ammonium pulse technique, radioactive or nonradioactive rubidium ion uptake-assay, and thallium ion-uptake assay. CCCs' activity can also be indirectly observed by measuring γ-aminobutyric acid (GABA) activity with patch-clamp electrophysiology and intracellular chloride concentration with sensitive microelectrodes, radiotracer Cl, and fluorescent dyes. Other techniques include directly looking at kinase regulatory sites phosphorylation, flame photometry, Na uptake assay, structural biology, molecular modeling, and high-throughput drug screening. This review summarizes the role of CCCs in genetic disorders and cell volume regulation, current methods applied in studying CCCs biology, and compounds developed that directly or indirectly target the CCCs for disease treatments.
PubMed: 38223443
DOI: 10.1016/j.jpha.2023.09.002 -
Stroke Oct 2023Spreading depolarizations (SDs) occur in all types of brain injury and may be associated with detrimental effects in ischemic stroke and subarachnoid hemorrhage. While...
BACKGROUND
Spreading depolarizations (SDs) occur in all types of brain injury and may be associated with detrimental effects in ischemic stroke and subarachnoid hemorrhage. While rapid hematoma growth during intracerebral hemorrhage triggers SDs, their role in intracerebral hemorrhage is unknown.
METHODS
We used intrinsic optical signal and laser speckle imaging, combined with electrocorticography, to investigate the effects of SD on hematoma growth during the hyperacute phase (0-4 hours) after intracortical collagenase injection in mice. Hematoma expansion, SDs, and cerebral blood flow were simultaneously monitored under normotensive and hypertensive conditions.
RESULTS
Spontaneous SDs erupted from the vicinity of the hematoma during rapid hematoma growth. We found that hematoma growth slowed down by >60% immediately after an SD. This effect was even stronger in hypertensive animals with faster hematoma growth. To establish causation, we exogenously induced SDs (every 30 minutes) at a remote site by topical potassium chloride application and found reduced hematoma growth rate and final hemorrhage volume (18.2±5.8 versus 10.7±4.1 mm). Analysis of cerebral blood flow using laser speckle flowmetry revealed that suppression of hematoma growth by spontaneous or induced SDs coincided and correlated with the characteristic oligemia in the wake of SD, implicating the vasoconstrictive effect of SD as one potential mechanism of action.
CONCLUSIONS
Our findings reveal that SDs limit hematoma growth during the early hours of intracerebral hemorrhage and decrease final hematoma volume.
Topics: Mice; Animals; Cortical Spreading Depression; Subarachnoid Hemorrhage; Electrocorticography; Cerebral Hemorrhage; Hematoma
PubMed: 37610105
DOI: 10.1161/STROKEAHA.123.042632 -
The Journal of Biological Chemistry Nov 2023Chloride intracellular channels (CLICs) are a family of proteins that exist in soluble and transmembrane forms. The newest discovered member of the family CLIC6 is...
Chloride intracellular channels (CLICs) are a family of proteins that exist in soluble and transmembrane forms. The newest discovered member of the family CLIC6 is implicated in breast, ovarian, lung gastric, and pancreatic cancers and is also known to interact with dopamine-(D(2)-like) receptors. The soluble structure of the channel has been resolved, but the exact physiological role of CLIC6, biophysical characterization, and the membrane structure remain unknown. Here, we aimed to characterize the biophysical properties of this channel using a patch-clamp approach. To determine the biophysical properties of CLIC6, we expressed CLIC6 in HEK-293 cells. On ectopic expression, CLIC6 localizes to the plasma membrane of HEK-293 cells. We established the biophysical properties of CLIC6 by using electrophysiological approaches. Using various anions and potassium (K) solutions, we determined that CLIC6 is more permeable to chloride-(Cl) as compared to bromide-(Br), fluoride-(F), and K ions. In the whole-cell configuration, the CLIC6 currents were inhibited after the addition of 10 μM of IAA-94 (CLIC-specific blocker). CLIC6 was also found to be regulated by pH and redox potential. We demonstrate that the histidine residue at 648 (H648) in the C terminus and cysteine residue in the N terminus (C487) are directly involved in the pH-induced conformational change and redox regulation of CLIC6, respectively. Using qRT-PCR, we identified that CLIC6 is most abundant in the lung and brain, and we recorded the CLIC6 current in mouse lung epithelial cells. Overall, we have determined the biophysical properties of CLIC6 and established it as a Cl channel.
Topics: Animals; Humans; Mice; Anions; Chloride Channels; Chlorides; Epithelial Cells; HEK293 Cells
PubMed: 37838179
DOI: 10.1016/j.jbc.2023.105349 -
Medicina Clinica Jan 2024
Topics: Humans; Diuretics; Heart Failure; Drug Resistance; Sodium Potassium Chloride Symporter Inhibitors
PubMed: 37919121
DOI: 10.1016/j.medcli.2023.10.001 -
Hypertension Research : Official... Jun 2024
PubMed: 38914705
DOI: 10.1038/s41440-024-01757-w -
Pharmacological Research Aug 2023Malignant proliferation and metastasis are the main causes of breast cancer death. The transcription factor high mobility group (HMG) box-containing protein 1 (HBP1) is...
Malignant proliferation and metastasis are the main causes of breast cancer death. The transcription factor high mobility group (HMG) box-containing protein 1 (HBP1) is an important tumor suppressor whose deletion or mutation is closely related to the appearance of tumors. Here, we investigated the role of HBP1 in breast cancer suppression. HBP1 enhances the activity of the tissue inhibitors of metalloproteinases 3 (TIMP3) promoter, thereby increasing protein and mRNA levels of TIMP3. TIMP3 increases the phosphatase and tensin homolog (PTEN) protein level by inhibiting its degradation and acts as a metalloproteinase inhibitor to inhibit the protein levels of MMP2/9. In this study, we demonstrated that the HBP1/TIMP3 axis plays a crucial role in inhibiting the tumorigenesis of breast cancer. HBP1 deletion interferes with the regulation of the axis and induces the occurrence and malignant progression of breast cancer. In addition, the HBP1/TIMP3 axis promotes the sensitivity of breast cancer to radiation therapy and hormone therapy. Our study opens new perspectives on the treatment and prognosis of breast cancer.
Topics: Humans; Female; Breast Neoplasms; RNA, Messenger; Prognosis; Promoter Regions, Genetic; High Mobility Group Proteins; Repressor Proteins; Tissue Inhibitor of Metalloproteinase-3
PubMed: 37414199
DOI: 10.1016/j.phrs.2023.106846 -
BMC Nephrology Jul 2023Studies reported that kelch-like protein 3 (KLHL3)-Cullin3(CUL3) E3 ligase ubiquitinated with-no-lysine kinase 4 (WNK4). Impaired WNK4 ubiquitination plays a key role in...
BACKGROUND
Studies reported that kelch-like protein 3 (KLHL3)-Cullin3(CUL3) E3 ligase ubiquitinated with-no-lysine kinase 4 (WNK4). Impaired WNK4 ubiquitination plays a key role in Familial hyperkalemic hypertension (FHHt, also called pseudohypoaldosteronism type II) which results from overaction of thiazide-sensitive sodium chloride cotransport (NCC). In addition, researchers have also found that dietary potassium deficiency activates NCC along the renal distal convoluted tubule (DCT). However, the underlying mechanism remains unclear about the relationship between potassium and WNK4.
METHODS
In the present study, we conducted in vitro and in vivo experiments to confirm that KLHL3-dependent WNK4 degradation is affected by potassium through the neddylation and autophagy pathway. In vitro, the WNK4 and KLHL3 plasmids were cotransfected into HEK293 cell lines by lipofectamine 2000, and then incubated with different potassium concentrations (1mmol/L and 10mmol/L) for 24 h, and further treated with MLN4924 or the autophagy inhibitor or both of MLN4924 and the autophagy inhibitor for another 24 h respectively. In vivo, we created mice that were fed with low or high potassium diets and then were injected MLN4924 in the experimental groups. The expression of WNK4, pWNK4, KLHL3, NEDD8, LC3 ,and P62 was detected by western blotting in vitro and vivo experiments.
RESULTS
We found that the abundance and phosphorylation of WNK4 increase when neddylation is inhibited both in vitro and vivo. Furthermore, the abundance of pWNK4, WNK4, NEDD8, and KLHL3 was increased in the low potassium (LK) group. Inhibiting autophagy can ameliorate the effect of potassium on the abundance and activity of WNK4 to some extent.
CONCLUSION
These findings suggest a complex regulation of potassium in the degradation of WNK4. Low potassium can activate WNK4, which may be related to neddylation and autophagy, but the mechanism needs to be further studied.
Topics: Animals; Humans; Mice; Adaptor Proteins, Signal Transducing; Autophagy; HEK293 Cells; Kidney Tubules, Distal; Microfilament Proteins; Potassium; Protein Serine-Threonine Kinases
PubMed: 37481568
DOI: 10.1186/s12882-023-03257-4 -
European Journal of Heart Failure Aug 2023Acetazolamide, an inhibitor of proximal tubular sodium reabsorption, leads to more effective decongestion in acute heart failure (AHF). It is unknown whether... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
Acetazolamide, an inhibitor of proximal tubular sodium reabsorption, leads to more effective decongestion in acute heart failure (AHF). It is unknown whether acetazolamide alters serum sodium and potassium levels on top of loop diuretics and if baseline values modify the treatment effect of acetazolamide.
METHODS AND RESULTS
This is a pre-specified sub-analysis of the ADVOR trial that randomized 519 patients with AHF and volume overload in a 1:1 ratio to intravenous acetazolamide or matching placebo on top of standardized intravenous loop diuretics. Mean potassium and sodium levels at randomization were 4.2 ± 0.6 and 139 ± 4 mmol/L in the acetazolamide arm versus 4.2 ± 0.6 and 140 ± 4 mmol/L in the placebo arm. Hypokalaemia (<3.5 mmol/L) on admission was present in 44 (9%) patients and hyponatraemia (≤135 mmol/L) in 82 (16%) patients. After 3 days of treatment, 44 (17%) patients in the acetazolamide arm and 35 (14%) patients in the placebo arm developed hyponatraemia (p = 0.255). Patients randomized to acetazolamide demonstrated a slight decrease in mean potassium levels during decongestion, which was non-significant over time (p = 0.053) and had no significant impact on hypokalaemia incidence (p = 0.061). Severe hypokalaemia (<3.0 mmol/L) occurred in only 7 (1%) patients, similarly distributed between the two treatment arms (p = 0.676). Randomization towards acetazolamide improved decongestive response irrespective of baseline serum sodium and potassium levels.
CONCLUSIONS
Acetazolamide on top of standardized loop diuretic therapy does not lead to clinically important hypokalaemia or hyponatraemia and improves decongestion over the entire range of baseline serum potassium and sodium levels.
Topics: Humans; Acetazolamide; Heart Failure; Sodium; Sodium Potassium Chloride Symporter Inhibitors; Hyponatremia; Hypokalemia; Potassium; Diuretics
PubMed: 37062871
DOI: 10.1002/ejhf.2863 -
Hypertension (Dallas, Tex. : 1979) Mar 2024Excessive salt intake raises blood pressure, but the implications of this observation for human health have remained contentious. It has also been recognized for many... (Review)
Review
Excessive salt intake raises blood pressure, but the implications of this observation for human health have remained contentious. It has also been recognized for many years that potassium intake may mitigate the effects of salt intake on blood pressure and possibly on outcomes such as stroke. Recent large randomized intervention trials have provided strong support for the benefits of replacing salt (NaCl) with salt substitute (75% NaCl, 25% KCl) on hard outcomes, including stroke. During the same period of time, major advances have been made in understanding how the body senses and tastes salt, and how these sensations drive intake. Additionally, new insights into the complex interactions between systems that control sodium and potassium excretion by the kidneys, and the brain have highlighted the existence of a potassium switch in the kidney distal nephron. This switch seems to contribute importantly to the blood pressure-lowering effects of potassium intake. In recognition of these evolving data, the United States Food and Drug Administration is moving to permit potassium-containing salt substitutes in food manufacturing. Given that previous attempts to reduce salt consumption have not been successful, this new approach has a chance of improving health and ending the 'Salt Wars'.
Topics: Humans; Sodium, Dietary; Sodium Chloride, Dietary; Hypertension; Sodium Chloride; Blood Pressure; Potassium; Stroke; Potassium, Dietary
PubMed: 37823260
DOI: 10.1161/HYPERTENSIONAHA.123.19487