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Nature Cell Biology Dec 2019Apoptotic cell clearance (efferocytosis) elicits an anti-inflammatory response by phagocytes, but the mechanisms that underlie this response are still being defined....
Apoptotic cell clearance (efferocytosis) elicits an anti-inflammatory response by phagocytes, but the mechanisms that underlie this response are still being defined. Here, we uncover a chloride-sensing signalling pathway that controls both the phagocyte 'appetite' and its anti-inflammatory response. Efferocytosis transcriptionally altered the genes that encode the solute carrier (SLC) proteins SLC12A2 and SLC12A4. Interfering with SLC12A2 expression or function resulted in a significant increase in apoptotic corpse uptake per phagocyte, whereas the loss of SLC12A4 inhibited corpse uptake. In SLC12A2-deficient phagocytes, the canonical anti-inflammatory program was replaced by pro-inflammatory and oxidative-stress-associated gene programs. This 'switch' to pro-inflammatory sensing of apoptotic cells resulted from the disruption of the chloride-sensing pathway (and not due to corpse overload or poor degradation), including the chloride-sensing kinases WNK1, OSR1 and SPAK-which function upstream of SLC12A2-had a similar effect on efferocytosis. Collectively, the WNK1-OSR1-SPAK-SLC12A2/SLC12A4 chloride-sensing pathway and chloride flux in phagocytes are key modifiers of the manner in which phagocytes interpret the engulfed apoptotic corpse.
Topics: Animals; Apoptosis; Biological Transport; Cell Line; Cell Line, Tumor; Chlorides; Humans; Inflammation; Jurkat Cells; Mice; Mice, Inbred C57BL; Oxidative Stress; Phagocytes; Phagocytosis; Signal Transduction; Sodium-Potassium-Chloride Symporters; Transcription, Genetic
PubMed: 31792382
DOI: 10.1038/s41556-019-0431-1 -
International Journal of Molecular... Jan 2021Stroke is one of the major culprits responsible for morbidity and mortality worldwide, and the currently available pharmacological strategies to combat this global... (Review)
Review
Stroke is one of the major culprits responsible for morbidity and mortality worldwide, and the currently available pharmacological strategies to combat this global disease are scanty. Cation-chloride cotransporters (CCCs) are expressed in several tissues (including neurons) and extensively contribute to the maintenance of numerous physiological functions including chloride homeostasis. Previous studies have implicated two CCCs, the Na-K-Cl and K-Cl cotransporters (NKCCs and KCCs) in stroke episodes along with their upstream regulators, the with-no-lysine kinase (WNKs) family and STE20/SPS1-related proline/alanine rich kinase (SPAK) or oxidative stress response kinase (OSR1) via a signaling pathway. As the WNK-SPAK/OSR1 pathway reciprocally regulates NKCC and KCC, a growing body of evidence implicates over-activation and altered expression of NKCC1 in stroke pathology whilst stimulation of KCC3 during and even after a stroke event is neuroprotective. Both inhibition of NKCC1 and activation of KCC3 exert neuroprotection through reduction in intracellular chloride levels and thus could be a novel therapeutic strategy. Hence, this review summarizes the current understanding of functional regulations of the CCCs implicated in stroke with particular focus on NKCC1, KCC3, and WNK-SPAK/OSR1 signaling and discusses the current and potential pharmacological treatments for stroke.
Topics: Homeostasis; Humans; Neurons; Phosphorylation; Protein Serine-Threonine Kinases; Signal Transduction; Sodium Potassium Chloride Symporter Inhibitors; Sodium-Potassium-Chloride Symporters; Stroke; Symporters; WNK Lysine-Deficient Protein Kinase 1; K Cl- Cotransporters
PubMed: 33513812
DOI: 10.3390/ijms22031232 -
Hypertension (Dallas, Tex. : 1979) Mar 2024Excess dietary sodium intake and insufficient dietary potassium intake are both well-established risk factors for hypertension. Despite some successful initiatives,... (Review)
Review
Excess dietary sodium intake and insufficient dietary potassium intake are both well-established risk factors for hypertension. Despite some successful initiatives, efforts to control hypertension by improving dietary intake have largely failed because the changes required are mostly too hard to implement. Consistent recent data from randomized controlled trials show that potassium-enriched, sodium-reduced salt substitutes are an effective option for improving consumption levels and reducing blood pressure and the rates of cardiovascular events and deaths. Yet, salt substitutes are inconsistently recommended and rarely used. We sought to define the extent to which evidence about the likely benefits and harms of potassium-enriched salt substitutes has been incorporated into clinical management by systematically searching guidelines for the management of hypertension or chronic kidney disease. We found incomplete and inconsistent recommendations about the use of potassium-enriched salt substitutes in the 32 hypertension and 14 kidney guidelines that we reviewed. Discussion among the authors identified the possibility of updating clinical guidelines to provide consistent advice about the use of potassium-enriched salt for hypertension control. Draft wording was chosen to commence debate and progress consensus building: strong recommendation for patients with hypertension-potassium-enriched salt with a composition of 75% sodium chloride and 25% potassium chloride should be recommended to all patients with hypertension, unless they have advanced kidney disease, are using a potassium supplement, are using a potassium-sparing diuretic, or have another contraindication. We strongly encourage clinical guideline bodies to review their recommendations about the use of potassium-enriched salt substitutes at the earliest opportunity.
Topics: Humans; Potassium; Hypertension; Diet; Potassium Chloride; Renal Insufficiency, Chronic; Sodium Chloride, Dietary; Blood Pressure
PubMed: 38284271
DOI: 10.1161/HYPERTENSIONAHA.123.21343 -
ASN Neuro 2020Elevated extracellular potassium chloride is widely used to achieve membrane depolarization of cultured neurons. This technique has illuminated mechanisms of calcium... (Review)
Review
Elevated extracellular potassium chloride is widely used to achieve membrane depolarization of cultured neurons. This technique has illuminated mechanisms of calcium influx through L-type voltage sensitive calcium channels, activity-regulated signaling, downstream transcriptional events, and many other intracellular responses to depolarization. However, there is enormous variability in these treatments, including durations from seconds to days and concentrations from 3mM to 150 mM KCl. Differential effects of these variable protocols on neuronal activity and transcriptional programs are underexplored. Furthermore, potassium chloride treatments are criticized for being poor representatives of phenomena and are questioned for their effects on cell viability. In this review, we discuss the intracellular consequences of elevated extracellular potassium chloride treatment , the variability of such treatments in the literature, the strengths and limitations of this tool, and relevance of these studies to brain functions and dysfunctions.
Topics: Action Potentials; Animals; Calcium Channels, L-Type; Humans; Membrane Potentials; Neuromuscular Depolarizing Agents; Neurons; Potassium Chloride
PubMed: 33256465
DOI: 10.1177/1759091420974807 -
International Journal of Nephrology and... 2023Chloride anions are the most abundant in humans. For many years, it has been believed that chloride is simply a counterion of all other cations, ensuring the... (Review)
Review
Chloride anions are the most abundant in humans. For many years, it has been believed that chloride is simply a counterion of all other cations, ensuring the electroneutrality of the extracellular space. Recent data suggests that chloride anions possess a broad spectrum of important activities that regulate vital cellular functions. It is now evident that, apart from its contribution to the electroneutrality of the extracellular space, it acts as an osmole and contributes to extracellular and intracellular volume regulation. Its anionic charge also contributes to the generation of cell membrane potential. The most interesting action of chloride anions is their ability to regulate the activity of with-no-lysine kinases, which in turn regulate the activity of sodium chloride and potassium chloride cotransporters and govern the reabsorption of salt and excretion of potassium by nephron epithelia. Chloride anions seem to play a crucial role in cell functions, such as cell volume regulation, sodium reabsorption in the distal nephron, potassium balance, and sodium sensitivity, which lead to hypertension. All of these functions are accomplished on a molecular level via complicated metabolic pathways, many of which remain poorly defined. We attempted to elucidate some of these pathways in light of recent advances in our knowledge, obtained mainly from experimental studies.
PubMed: 37601040
DOI: 10.2147/IJNRD.S417766 -
Current Opinion in Nephrology and... Sep 2022Existing guidelines offer little direction about the use of thiazide and loop diuretics in patients with chronic kidney disease (CKD). This review summarizes recent... (Review)
Review
PURPOSE OF REVIEW
Existing guidelines offer little direction about the use of thiazide and loop diuretics in patients with chronic kidney disease (CKD). This review summarizes recent studies impacting indications and safety considerations for these agents in patients with CKD.
RECENT FINDINGS
Chlorthalidone reduces blood pressure compared to placebo in patients with advanced CKD, challenging the belief that thiazide diuretics lose efficacy at lower glomerular filtration rates (GFR). Existing studies show no clear impact of thiazide or loop diuretic use on kidney or cardiovascular outcomes in patients with CKD. Sodium-glucose co-transporter type 2 (SGLT2) inhibitors have diuretic effects, but concomitant use of a diuretic does not diminish the preventive benefits of these agents against acute kidney injury (AKI). Despite theoretical concerns, thiazide diuretics likely do not worsen circulating vasopressin levels or cyst progression in polycystic kidney disease and may be useful for alleviating polyuria from tolvaptan. Diuretics cause multiple adverse effects, including electrolyte abnormalities, hemodynamic-mediated decrease in estimated GFR, and AKI.
SUMMARY
Recent evidence supports expanded indications for diuretics in patients with kidney disease, including chlorthalidone for hypertension in advanced CKD. Monitoring electrolytes and estimated GFR is critical to ensure patient safety when prescribing these agents for patients with CKD.
Topics: Acute Kidney Injury; Chlorthalidone; Diuretics; Humans; Hypertension; Renal Insufficiency, Chronic; Sodium Chloride Symporter Inhibitors; Sodium Potassium Chloride Symporter Inhibitors; Sodium-Glucose Transporter 2 Inhibitors; Thiazides
PubMed: 35894274
DOI: 10.1097/MNH.0000000000000814 -
Kidney360 Nov 2022Elevated abundance of sodium-chloride cotransporter (NCC) and phosphorylated NCC (pNCC) are potential markers of primary aldosteronism (PA), but these effects may be...
BACKGROUND
Elevated abundance of sodium-chloride cotransporter (NCC) and phosphorylated NCC (pNCC) are potential markers of primary aldosteronism (PA), but these effects may be driven by hypokalemia.
METHODS
We measured plasma potassium in patients with PA. If potassium was <4.0 mmol/L, patients were given sufficient oral potassium chloride (KCl) over 24 hours to achieve as close to 4.0 mmol/L as possible. Clinical chemistries were assessed, and urinary extracellular vesicles (uEVs) were examined to investigate effects on NCC.
RESULTS
Among 21 patients with PA who received a median total dose of 6.0 g (2.4-16.8 g) of KCl, increases were observed in plasma potassium (from 3.4 to 4.0 mmol/L; <0.001), aldosterone (from 305 to 558 pmol/L; 0.01), and renin (from 1.2 to 2.5 mIU/L; <0.001), whereas decreases were detected in uEV levels of NCC (median fold change [FC]=0.71 [0.09-1.99]; 0.02), pT60-NCC (FC=0.84 [0.06-1.66]; 0.05), and pT55/60-NCC (FC=0.67 [0.08-2.42]; 0.02). By contrast, in 10 patients with PA who did not receive KCl, there were no apparent changes in plasma potassium, NCC abundance, and phosphorylation status, but increases were observed in plasma aldosterone (from 178 to 418 pmol/L; 0.006) and renin (from 2.0 to 3.0 mU/L; 0.009). Plasma potassium correlated inversely with uEV levels of NCC ( =0.11; 0.01), pT60-NCC ( =0.11; =0.01), and pT55/60-NCC ( =0.11; =0.01).
CONCLUSIONS
Acute oral KCl loading replenished plasma potassium in patients with PA and suppressed NCC abundance and phosphorylation, despite a significant rise in plasma aldosterone. This supports the view that potassium supplementation in humans with PA overrides the aldosterone stimulatory effect on NCC. The increased plasma aldosterone in patients with PA without KCl supplementation may be due to aldosterone response to posture challenge.
Topics: Humans; Sodium Chloride Symporters; Aldosterone; Potassium Chloride; Renin; Phosphorylation; Potassium; Hyperaldosteronism; Dietary Supplements
PubMed: 36514401
DOI: 10.34067/KID.0003632022 -
Cardiorenal Medicine 2021Clinical guidelines include diuretics for the treatment of heart failure (HF), not to decrease mortality but to decrease symptoms and hospitalizations. More attention... (Review)
Review
Clinical guidelines include diuretics for the treatment of heart failure (HF), not to decrease mortality but to decrease symptoms and hospitalizations. More attention has been paid to the worse outcomes, including mortality, associated with continual diuretic therapy due to hypochloremia. Studies have revealed a pivotal role for serum chloride in the pathophysiology of HF and is now a target of treatment to decrease mortality. The prognostic value of serum chloride in HF has been the subject of much attention. Mechanistically, the macula densa, a region in the renal juxtaglomerular apparatus, relies on chloride levels to sense salt and volume status. The recent discovery of with-no-lysine (K) (WNK) protein kinase as an intracellular chloride sensor sheds light on the possible reason of diuretic resistance in HF. The action of chloride on WNKs results in the upregulation of the sodium-potassium-chloride cotransporter and sodium-chloride cotransporter receptors, which could lead to increased electrolyte and fluid reabsorption. Genetic studies have revealed that a variant of a voltage-sensitive chloride channel (CLCNKA) gene leads to almost a 50% decrease in current amplitude and function of the renal chloride channel. This variant increases the risk of HF. Several trials exploring the prognostic value of chloride in both acute and chronic HF have shown mostly positive results, some even suggesting a stronger role than sodium. However, so far, interventional trials exploring serum chloride as a therapeutic target have been largely inconclusive. This study is a review of the pathophysiologic effects of hypochloremia in HF, the genetics of chloride channels, and clinical trials that are underway to investigate novel approaches to HF management.
Topics: Chlorides; Diuretics; Heart Failure; Humans; Sodium; Water-Electrolyte Imbalance
PubMed: 33873189
DOI: 10.1159/000515604 -
American Journal of Physiology. Renal... Dec 2020Similar to other organs, renal lymphatics remove excess fluid, solutes, and macromolecules from the renal interstitium. Given the kidney's unique role in maintaining...
Similar to other organs, renal lymphatics remove excess fluid, solutes, and macromolecules from the renal interstitium. Given the kidney's unique role in maintaining body fluid homeostasis, renal lymphatics may be critical in this process. However, little is known regarding the pathways involved in renal lymphatic vessel function, and there are no studies on the effects of drugs targeting impaired interstitial clearance, such as diuretics. Using pressure myography, we showed that renal lymphatic collecting vessels are sensitive to changes in transmural pressure and have an optimal range of effective pumping. In addition, they are responsive to vasoactive factors known to regulate tone in other lymphatic vessels including prostaglandin E and nitric oxide, and their spontaneous contractility requires Ca and Cl. We also demonstrated that Na-K-2Cl cotransporter Nkcc1, but not Nkcc2, is expressed in extrarenal lymphatic vessels. Furosemide, a loop diuretic that inhibits Na-K-2Cl cotransporters, induced a dose-dependent dilation in lymphatic vessels and decreased the magnitude and frequency of spontaneous contractions, thereby reducing the ability of these vessels to propel lymph. Ethacrynic acid, another loop diuretic, had no effect on vessel tone. These data represent a significant step forward in our understanding of the mechanisms underlying renal lymphatic vessel function and highlight potential off-target effects of furosemide that may exacerbate fluid accumulation in edema-forming conditions.
Topics: Animals; Calcium; Chlorides; Furosemide; Kidney; Lymphatic Vessels; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Pressure; Rats; Rats, Sprague-Dawley; Sodium Potassium Chloride Symporter Inhibitors
PubMed: 33103446
DOI: 10.1152/ajprenal.00322.2020 -
Kidney International Reports Jun 2023The putative "renal-K switch" mechanism links dietary potassium intake with sodium retention and involves activation of the sodium chloride (NaCl) cotransporter (NCC) in...
INTRODUCTION
The putative "renal-K switch" mechanism links dietary potassium intake with sodium retention and involves activation of the sodium chloride (NaCl) cotransporter (NCC) in the distal convoluted tubule in response to low potassium intake, and suppression in response to high potassium intake. This study examined NCC abundance and phosphorylation (phosphorylated NCC [pNCC]) in urinary extracellular vesicles (uEVs) isolated from healthy adults on a high sodium diet to determine tubular responses to alteration in potassium chloride (KCl) intake.
METHODS
Healthy adults maintained on a high sodium (∼4.5 g [200 mmol]/d) low potassium (∼2.3 g [60 mmol]/d) diet underwent a 5-day run-in period followed by a crossover study, with 5-day supplementary KCl (active phase, Span-K 3 tablets (potassium 24 mmol) thrice daily) or 5-day placebo administrated in random order and separated by 2-day washout. Ambulatory blood pressure (BP) and biochemistries were assessed, and uEVs were analyzed by western blotting.
RESULTS
Among the 18 participants who met analysis criteria, supplementary KCl administration (vs. placebo) was associated with markedly higher levels of plasma potassium and 24-hour urine excretion of potassium, chloride, and aldosterone. KCl supplementation was associated with lower uEV levels of NCC (median fold change = 0.74 [0.30-1.69], < 0.01) and pNCC (fold change = 0.81 [0.19-1.75], < 0.05). Plasma potassium inversely correlated with uEV NCC (R = 0.11, = 0.05).
CONCLUSIONS
The lower NCC and pNCC in uEVs in response to oral KCl supplementation provide evidence to support the hypothesis of a functional "renal-K switch" in healthy human subjects.
PubMed: 37284683
DOI: 10.1016/j.ekir.2023.03.011