{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T03:14:09Z","timestamp":1788146049078,"version":"build-2803163510"},"reference-count":166,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007045","name":"SECIHTI","doi-asserted-by":"publisher","award":["CF-2023-I-532"],"award-info":[{"award-number":["CF-2023-I-532"]}],"id":[{"id":"10.13039\/501100007045","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007045","name":"SECIHTI","doi-asserted-by":"publisher","award":["INC-24-1422"],"award-info":[{"award-number":["INC-24-1422"]}],"id":[{"id":"10.13039\/501100007045","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007045","name":"SECIHTI","doi-asserted-by":"publisher","award":["CBF-2025-G-704"],"award-info":[{"award-number":["CBF-2025-G-704"]}],"id":[{"id":"10.13039\/501100007045","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007045","name":"SECIHTI","doi-asserted-by":"publisher","award":["4078310"],"award-info":[{"award-number":["4078310"]}],"id":[{"id":"10.13039\/501100007045","id-type":"DOI","asserted-by":"publisher"}]},{"name":"PAPIIT","award":["INN228123"],"award-info":[{"award-number":["INN228123"]}]},{"DOI":"10.13039\/501100015773","name":"Instituto Nacional de Cardiolog\u00eda Ignacio Ch\u00e1vez","doi-asserted-by":"publisher","award":["INC-24-1422"],"award-info":[{"award-number":["INC-24-1422"]}],"id":[{"id":"10.13039\/501100015773","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Cardiomyopathies are a major category of cardiovascular disease, significantly contributing to global morbidity and mortality. Their pathogenesis involves a complex interplay of genetic and environmental factors, with multiple gene families playing critical roles in disease progression. Among these, the Solute Carrier 12A (SLC12A) family encodes membrane cation-coupled chloride cotransporters (CCCs), which are essential for ion transport and cellular homeostasis. By regulating intracellular chloride and potassium concentrations, SLC12A\/CCC transporters may directly influence myocardial electrophysiology, repolarization dynamics, and susceptibility to cardiomyopathies. Dysfunction of potassium-handling cotransporters can disrupt action potential propagation, increasing the risk of arrhythmias, while chloride transport abnormalities exacerbate ischemic injury by impairing cell volume regulation and metabolic responses to hypoxia. This review examines the expression and protein levels of SLC12A\/CCCs in cardiac tissue, providing crucial insights into their functional significance for maintaining cardiac ion homeostasis. Understanding the regulatory mechanisms of these transporters could inform therapeutic interventions to restore ion balance and mitigate myocardial dysfunction in affected patients, thereby improving cardiac health.<\/jats:p>","DOI":"10.3390\/cells15171549","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T13:26:03Z","timestamp":1787837163000},"page":"1549","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Exploring the Role of the SLC12A Cation-Coupled Chloride Cotransporters in the Cardiovascular System"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6881-0160","authenticated-orcid":false,"given":"Adriana","family":"Mercado","sequence":"first","affiliation":[{"name":"Departamento de Bioqu\u00edmica, Instituto Nacional de Cardiolog\u00eda Ignacio Ch\u00e1vez, Tlalpan, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Adri\u00e1n","family":"Guti\u00e9rrez-Alejo","sequence":"additional","affiliation":[{"name":"Unidad de Investigaci\u00f3n UNAM-INC, Facultad de Medicina, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Mexico City 04510, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabina","family":"Orozco-Navarro","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica, Instituto Nacional de Cardiolog\u00eda Ignacio Ch\u00e1vez, Tlalpan, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6640-7100","authenticated-orcid":false,"given":"Paola de","family":"los Heros","sequence":"additional","affiliation":[{"name":"Unidad de Investigaci\u00f3n UNAM-INC, Facultad de Medicina, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Mexico City 04510, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1152\/physrev.00011.2004","article-title":"Molecular Physiology and Pathophysiology of Electroneutral Cation-Chloride Cotransporters","volume":"85","author":"Gamba","year":"2005","journal-title":"Physiol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/j.mam.2012.05.002","article-title":"The SLC12 Family of Electroneutral Cation-Coupled Chloride Cotransporters","volume":"34","author":"Arroyo","year":"2013","journal-title":"Mol. Asp. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"F131","DOI":"10.1152\/ajprenal.00071.2016","article-title":"Physiological Role of SLC12 Family Members in the Kidney","volume":"311","author":"Gamba","year":"2016","journal-title":"Am. J. Physiol.-Ren. Physiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.yjmcc.2013.04.011","article-title":"Na+ Transport in the Normal and Failing Heart\u2014Remember the Balance","volume":"61","author":"Despa","year":"2013","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.yjmcc.2013.06.003","article-title":"Cardiac Sodium Transport and Excitation\u2013Contraction Coupling","volume":"61","author":"Aronsen","year":"2013","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Meor Azlan, N.F., and Zhang, J. (2020). Role of the Cation-Chloride-Cotransporters in Cardiovascular Disease. Cells, 9.","DOI":"10.20944\/preprints202008.0457.v1"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"6035","DOI":"10.1038\/s41467-021-25942-4","article-title":"Compensatory Ion Transport Buffers Daily Protein Rhythms to Regulate Osmotic Balance and Cellular Physiology","volume":"12","author":"Stangherlin","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"S17","DOI":"10.3103\/S0096392524600741","article-title":"Structural basis and molecular mechanisms of Cl\u2212 transmembrane transport in cardiomyocytes","volume":"79","author":"Voronina","year":"2024","journal-title":"Mosc. Univ. Biol. Sci. Bull."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1113\/jphysiol.1996.sp021137","article-title":"Contribution of Shrinkage of Extracellular Space to Extracellular K+ Accumulation in Myocardial Ischaemia of the Rabbit","volume":"490","author":"Yan","year":"1996","journal-title":"J. Physiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"31303","DOI":"10.1074\/jbc.M803706200","article-title":"Impaired Cardiac Contractility in Mice Lacking Both the AE3 Cl\u2212\/HCO3\u2212 Exchanger and the NKCC1 Na+-K+-2Cl\u2212 Cotransporter","volume":"283","author":"Prasad","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1007\/s00232-004-0695-6","article-title":"Regulation of K-Cl Cotransport: From Function to Genes","volume":"201","author":"Adragna","year":"2004","journal-title":"J. Membr. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"C1180","DOI":"10.1152\/ajpcell.00274.2012","article-title":"K+-Cl\u2212 Cotransporter-2 KCC2 in Chicken Cardiomyocytes","volume":"303","author":"Antrobus","year":"2012","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"16355","DOI":"10.1074\/jbc.274.23.16355","article-title":"Cloning and Characterization of KCC3 and KCC4, New Members of the Cation-Chloride Cotransporter Gene Family","volume":"274","author":"Mount","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Garneau, A.P., Marcoux, A.-A., No\u00ebl, M., Frenette-Cotton, R., Drolet, M.-C., Couet, J., Larivi\u00e8re, R., and Isenring, P. (2016). Ablation of Potassium-Chloride Cotransporter Type 3 (Kcc3) in Mouse Causes Multiple Cardiovascular Defects and Isosmotic Polyuria. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0154398"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"S111","DOI":"10.3109\/07853890.2011.653395","article-title":"NKCC1 and Hypertension: Role in the Regulation of Vascular Smooth Muscle Contractions and Myogenic Tone","volume":"44","author":"Orlov","year":"2012","journal-title":"Ann. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"152045","DOI":"10.1016\/j.acthis.2023.152045","article-title":"KCCs, NKCCs, and NCC: Potential Targets for Cardiovascular Therapeutics? A Comprehensive Review of Cell and Region Specific Expression and Function","volume":"125","author":"Modi","year":"2023","journal-title":"Acta Histochem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"H641","DOI":"10.1152\/ajpheart.1998.275.2.H641","article-title":"\u03b11-Adrenergic Activation of Myocardial Na-K-2Cl Cotransport Involving Mitogen-Activated Protein Kinase","volume":"275","author":"Andersen","year":"1998","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1038\/ng0696-183","article-title":"Bartter\u2019s Syndrome, Hypokalaemic Alkalosis with Hypercalciuria, Is Caused by Mutations in the Na\u2013K\u20132CI Cotransporter NKCC2","volume":"13","author":"Simon","year":"1996","journal-title":"Nat. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/ng0196-24","article-title":"Gitelman\u2019s Variant of Barter\u2019s Syndrome, Inherited Hypokalaemic Alkalosis, Is Caused by Mutations in the Thiazide-Sensitive Na\u2013Cl Cotransporter","volume":"12","author":"Simon","year":"1996","journal-title":"Nat. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"F961","DOI":"10.1152\/ajprenal.1996.271.5.F961","article-title":"The Molecular Basis of Inherited Hypokalemic Alkalosis: Bartter\u2019s and Gitelman\u2019s Syndromes","volume":"271","author":"Simon","year":"1996","journal-title":"Am. J. Physiol.-Ren. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1007\/s00424-003-1066-3","article-title":"Molecular Physiology of Cation-Coupled Cl\u2212 Cotransport: The SLC12 Family","volume":"447","author":"Hebert","year":"2004","journal-title":"Pfl\u00fcg. Arch."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"17713","DOI":"10.1016\/S0021-9258(17)32499-7","article-title":"Molecular Cloning, Primary Structure, and Characterization of Two Members of the Mammalian Electroneutral Sodium-(Potassium)-Chloride Cotransporter Family Expressed in Kidney","volume":"269","author":"Gamba","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2201","DOI":"10.1073\/pnas.91.6.2201","article-title":"Molecular Cloning and Functional Expression of the Bumetanide-Sensitive Na-K-Cl Cotransporter","volume":"91","author":"Xu","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"16237","DOI":"10.1074\/jbc.271.27.16237","article-title":"Molecular Cloning and Functional Expression of the K-Cl Cotransporter from Rabbit, Rat, and Human","volume":"271","author":"Gillen","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"10661","DOI":"10.1074\/jbc.274.15.10661","article-title":"Cloning, Characterization, and Chromosomal Location of a Novel Human K+-Cl\u2212 Cotransporter","volume":"274","author":"Hiki","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"C1210","DOI":"10.1152\/ajpcell.1999.277.6.C1210","article-title":"Molecular Cloning and Functional Characterization of KCC3, a New K-Cl Cotransporter","volume":"277","author":"Race","year":"1999","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"16245","DOI":"10.1074\/jbc.271.27.16245","article-title":"Molecular Characterization of a Putative K-Cl Cotransporter in Rat Brain","volume":"271","author":"Payne","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/S0169-328X(02)00190-0","article-title":"Molecular, Functional, and Genomic Characterization of Human KCC2, the Neuronal K\u2013Cl Cotransporter","volume":"103","author":"Song","year":"2002","journal-title":"Mol. Brain Res."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Hartmann, A.-M., and Nothwang, H.G. (2015). Molecular and Evolutionary Insights into the Structural Organization of Cation Chloride Cotransporters. Front. Cell. Neurosci., 8.","DOI":"10.3389\/fncel.2014.00470"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"C921","DOI":"10.1152\/ajpcell.00089.2023","article-title":"SLC12A Cryo-EM: Analysis of Relevant Ion Binding Sites, Structural Domains, and Amino Acids","volume":"325","author":"Trejo","year":"2023","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1152\/physrev.1998.78.1.247","article-title":"Functional Significance of Cell Volume Regulatory Mechanisms","volume":"78","author":"Lang","year":"1998","journal-title":"Physiol. Rev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"C176","DOI":"10.1152\/ajpcell.1991.260.1.C176","article-title":"Role of Protein Phosphatase in Activation of KCl Cotransport in Human Erythrocytes","volume":"260","author":"Kaji","year":"1991","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1085\/jgp.95.6.1021","article-title":"Kinetics of Activation and Inactivation of Swelling-Stimulated K+\/Cl\u2212 Transport. The Volume-Sensitive Parameter Is the Rate Constant for Inactivation","volume":"95","author":"Jennings","year":"1990","journal-title":"J. Gen. Physiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"C926","DOI":"10.1152\/ajpcell.1999.277.5.C926","article-title":"Serine\/Threonine Protein Phosphatases and Regulation of K-Cl Cotransport in Human Erythrocytes","volume":"277","author":"Bize","year":"1999","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1007\/s002320001109","article-title":"Stimulation of Human Erythrocyte K-Cl Cotransport and Protein Phosphatase Type 2A by n-Ethylmaleimide: Role of Intracellular Mg++","volume":"177","author":"Bize","year":"2000","journal-title":"J. Membr. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"16795","DOI":"10.1074\/jbc.275.22.16795","article-title":"WNK1, a Novel Mammalian Serine\/Threonine Protein Kinase Lacking the Catalytic Lysine in Subdomain II","volume":"275","author":"Xu","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1006\/abbi.1998.0736","article-title":"Molecular Cloning and Characterization of a Novel Ste20-Related Protein Kinase Enriched in Neurons and Transporting Epithelia","volume":"355","author":"Ushiro","year":"1998","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"C670","DOI":"10.1152\/ajpcell.2001.281.2.C670","article-title":"Functional and Molecular Characterization of the K-Cl Cotransporter of Xenopus laevis Oocytes","volume":"281","author":"Mercado","year":"2001","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1976","DOI":"10.1073\/pnas.0510947103","article-title":"WNK3 Bypasses the Tonicity Requirement for K-Cl Cotransporter Activation via a Phosphatase-Dependent Pathway","volume":"103","author":"Kahle","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1903","DOI":"10.1007\/s00467-014-2956-7","article-title":"Gordon Syndrome: A Continuing Story","volume":"30","year":"2015","journal-title":"Pediatr. Nephrol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Mabillard, H., and Sayer, J.A. (2019). The Molecular Genetics of Gordon Syndrome. Genes, 10.","DOI":"10.3390\/genes10120986"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1038\/ng1002","article-title":"The K\u2013Cl Cotransporter KCC3 Is Mutant in a Severe Peripheral Neuropathy Associated with Agenesis of the Corpus Callosum","volume":"32","author":"Howard","year":"2002","journal-title":"Nat. Genet."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.brainres.2018.12.025","article-title":"Pathogenic Potential of Human SLC12A5 Variants Causing KCC2 Dysfunction","volume":"1710","author":"Fukuda","year":"2019","journal-title":"Brain Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.1152\/physrev.00025.2021","article-title":"Chloride Transporters Controlling Neuronal Excitability","volume":"103","author":"Pressey","year":"2023","journal-title":"Physiol. Rev."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"133","DOI":"10.34067\/KID.0000000000000307","article-title":"From Fish Physiology to Human Disease: The Discovery of the NCC, NKCC2, and the Cation-Coupled Chloride Cotransporters","volume":"5","author":"Gamba","year":"2024","journal-title":"Kidney360"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2028","DOI":"10.1021\/ja01565a079","article-title":"Benzothiadiazine Dioxides as Novel Diuretics","volume":"79","author":"Novello","year":"1957","journal-title":"J. Am. Chem. Soc."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1038\/208080b0","article-title":"Effect of \u2018Furosemid\u2019 on Chloride and Water Excretion in Single Nephrons of the Kidney of the Rat","volume":"208","author":"Malnic","year":"1965","journal-title":"Nature"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"F68","DOI":"10.1152\/ajprenal.00032.2003","article-title":"Ammonium Transport and pH Regulation by K+-Cl\u2212 Cotransporters","volume":"285","author":"Bergeron","year":"2003","journal-title":"Am. J. Physiol.-Ren. Physiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.yjmcc.2021.08.003","article-title":"With a Grain of Salt: Sodium Elevation and Metabolic Remodelling in Heart Failure","volume":"161","author":"Shattock","year":"2021","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1098\/rsta.2006.1767","article-title":"Modelling Cl\u2212 Homeostasis and Volume Regulation of the Cardiac Cell","volume":"364","author":"Terashima","year":"2006","journal-title":"Phil. Trans. R. Soc. A"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"C869","DOI":"10.1152\/ajpcell.1994.267.4.C869","article-title":"The Na-K-Cl Cotransporters","volume":"267","author":"Haas","year":"1994","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/S0008-6363(96)00048-X","article-title":"Cell Swelling and Ion Transport Pathways in Cardiac Myocytes","volume":"32","author":"Vandenberg","year":"1996","journal-title":"Cardiovasc. Res."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Lam, P., Newland, J., Faull, R.L.M., and Kwakowsky, A. (2023). Cation-Chloride Cotransporters KCC2 and NKCC1 as Therapeutic Targets in Neurological and Neuropsychiatric Disorders. Molecules, 28.","DOI":"10.3390\/molecules28031344"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Josiah, S.S., Meor Azlan, N.F., and Zhang, J. (2021). Targeting the WNK-SPAK\/OSR1 Pathway and Cation-Chloride Cotransporters for the Therapy of Stroke. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22031232"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"eadd7176","DOI":"10.1126\/sciadv.add7176","article-title":"Cryo-EM Structure of the Human Sodium-Chloride Cotransporter NCC","volume":"8","author":"Nan","year":"2022","journal-title":"Sci. Adv."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1113\/JP276807","article-title":"Physiological Roles and Molecular Mechanisms of K+-Cl\u2212 Cotransport in the Mammalian Kidney and Cardiovascular System: Where Are We?","volume":"597","author":"Garneau","year":"2019","journal-title":"J. Physiol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"C1516","DOI":"10.1152\/ajpcell.1997.273.5.C1516","article-title":"Functional Characterization of the Neuronal-Specific K-Cl Cotransporter: Implications for [K+]o Regulation","volume":"273","author":"Payne","year":"1997","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1074\/jbc.M509972200","article-title":"A C-Terminal Domain in KCC2 Confers Constitutive K+-Cl\u2212 Cotransport","volume":"281","author":"Mercado","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"H1354","DOI":"10.1152\/ajpheart.00549.2003","article-title":"\u03b11-AR-Mediated Activation of NKCC in Rat Cardiomyocytes Involves ERK-Dependent Phosphorylation of the Cotransporter","volume":"286","author":"Andersen","year":"2004","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"F1402","DOI":"10.1152\/ajprenal.00390.2013","article-title":"Molecular Evidence for a Role for K+-Cl\u2212 Cotransporters in the Kidney","volume":"305","author":"Melo","year":"2013","journal-title":"Am. J. Physiol.-Ren. Physiol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1097\/MNH.0000000000000911","article-title":"The K\u2013Cl Cotransporter-3 in the Mammalian Kidney","volume":"32","author":"Ferdaus","year":"2023","journal-title":"Curr. Opin. Nephrol. Hypertens."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"C1171","DOI":"10.1152\/ajpcell.00094.2023","article-title":"Bicarbonate Is the Primary Inducer of KCC3a Expression in Renal Cortical B-Type Intercalated Cells","volume":"324","author":"Ferdaus","year":"2023","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Ferdaus, M.Z., Terker, A.S., Koumangoye, R., and Delpire, E. (2022). KCC3a, a Strong Candidate Pathway for K+ Loss in Alkalemia. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.931326"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1038\/416874a","article-title":"Deafness and Renal Tubular Acidosis in Mice Lacking the K-Cl Co-Transporter Kcc4","volume":"416","author":"Boettger","year":"2002","journal-title":"Nature"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1038\/s41586-019-1438-2","article-title":"Structure and Mechanism of the Cation\u2013Chloride Cotransporter NKCC1","volume":"572","author":"Chew","year":"2019","journal-title":"Nature"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Serranilla, M., and Woodin, M.A. (2022). Striatal Chloride Dysregulation and Impaired GABAergic Signaling Due to Cation-Chloride Cotransporter Dysfunction in Huntington\u2019s Disease. Front. Cell. Neurosci., 15.","DOI":"10.3389\/fncel.2021.817013"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"C337","DOI":"10.1152\/ajpcell.1985.249.3.C337","article-title":"Potassium-Chloride Cotransport in Cultured Chick Heart Cells","volume":"249","author":"Jacob","year":"1985","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.cmet.2017.01.007","article-title":"WNK Kinase Signaling in Ion Homeostasis and Human Disease","volume":"25","author":"Shekarabi","year":"2017","journal-title":"Cell Metab."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"626","DOI":"10.14336\/AD.2018.0928","article-title":"The WNK-SPAK\/OSR1 Kinases and the Cation-Chloride Cotransporters as Therapeutic Targets for Neurological Diseases","volume":"10","author":"Huang","year":"2019","journal-title":"Aging Dis."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1146\/annurev-physiol-031522-080651","article-title":"Intracellular Ion Control of WNK Signaling","volume":"85","author":"Goldsmith","year":"2023","journal-title":"Annu. Rev. Physiol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1038\/s41401-020-0474-7","article-title":"WNK-SPAK\/OSR1-NCC Kinase Signaling Pathway as a Novel Target for the Treatment of Salt-Sensitive Hypertension","volume":"42","author":"Brown","year":"2021","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1085\/jgp.97.4.799","article-title":"Okadaic Acid Inhibition of KCl Cotransport. Evidence That Protein Dephosphorylation Is Necessary for Activation of Transport by Either Cell Swelling or N-Ethylmaleimide","volume":"97","author":"Jennings","year":"1991","journal-title":"J. Gen. Physiol."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Murillo-de-Ozores, A.R., Ch\u00e1vez-Canales, M., De Los Heros, P., Gamba, G., and Casta\u00f1eda-Bueno, M. (2020). Physiological Processes Modulated by the Chloride-Sensitive WNK-SPAK\/OSR1 Kinase Signaling Pathway and the Cation-Coupled Chloride Cotransporters. Front. Physiol., 11.","DOI":"10.3389\/fphys.2020.585907"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/bs.ctm.2018.08.002","article-title":"Role of WNK Kinases in the Modulation of Cell Volume","volume":"Volume 81","author":"Gamba","year":"2018","journal-title":"Current Topics in Membranes"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"5562","DOI":"10.1038\/sj.onc.1204726","article-title":"WNK Kinases, a Novel Protein Kinase Subfamily in Multi-Cellular Organisms","volume":"20","author":"Jordan","year":"2001","journal-title":"Oncogene"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1912","DOI":"10.1126\/science.1075762","article-title":"The Protein Kinase Complement of the Human Genome","volume":"298","author":"Manning","year":"2002","journal-title":"Science"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1152\/physrev.00017.2010","article-title":"The WNKs: Atypical Protein Kinases with Pleiotropic Actions","volume":"91","author":"McCormick","year":"2011","journal-title":"Physiol. Rev."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1681\/ASN.2014050470","article-title":"The Effect of WNK4 on the Na+\u2013Cl\u2212 Cotransporter Is Modulated by Intracellular Chloride","volume":"26","author":"Argaiz","year":"2015","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"ra41","DOI":"10.1126\/scisignal.2005050","article-title":"Chloride Sensing by WNK1 Involves Inhibition of Autophosphorylation","volume":"7","author":"Piala","year":"2014","journal-title":"Sci. Signal."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"C371","DOI":"10.1152\/ajpcell.00488.2019","article-title":"WNK3 and WNK4 Exhibit Opposite Sensitivity with Respect to Cell Volume and Intracellular Chloride Concentration","volume":"319","author":"Mercado","year":"2020","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"18710","DOI":"10.1038\/srep18710","article-title":"Osmotic Stress Induces the Phosphorylation of WNK4 Ser575 via the p38MAPK-MK Pathway","volume":"6","author":"Maruyama","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"re3","DOI":"10.1126\/scisignal.2005365","article-title":"The WNK-SPAK\/OSR1 Pathway: Master Regulator of Cation-Chloride Cotransporters","volume":"7","author":"Alessi","year":"2014","journal-title":"Sci. Signal."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Goto, K., and Kitazono, T. (2022). Chloride Ions, Vascular Function and Hypertension. Biomedicines, 10.","DOI":"10.3390\/biomedicines10092316"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1016\/j.jchf.2021.07.006","article-title":"Chloride in Heart Failure","volume":"9","author":"Zandijk","year":"2021","journal-title":"JACC Heart Fail."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1007\/s40119-020-00194-3","article-title":"Hypochloraemia In Patients With Heart Failure: Causes And Consequences","volume":"9","author":"Cuthbert","year":"2020","journal-title":"Cardiol. Ther."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Nozaki, Y., Yoshihisa, A., Sato, Y., Ohara, H., Sugawara, Y., Abe, S., Misaka, T., Sato, T., Oikawa, M., and Kobayashi, A. (2023). Persistent Hypochloremia Is Associated with Adverse Prognosis in Patients Repeatedly Hospitalized for Heart Failure. J. Clin. Med., 12.","DOI":"10.3390\/jcm12041257"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Wu, L., Rodriguez, M., El Hachem, K., and Krittanawong, C. (2024). Diuretic Treatment in Heart Failure: A Practical Guide for Clinicians. J. Clin. Med., 13.","DOI":"10.3390\/jcm13154470"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"e003180","DOI":"10.1161\/CIRCHEARTFAILURE.116.003180","article-title":"Hypochloremia and Diuretic Resistance in Heart Failure: Mechanistic Insights","volume":"9","author":"Hanberg","year":"2016","journal-title":"Circ. Heart Fail."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1126\/science.1062844","article-title":"Human Hypertension Caused by Mutations in WNK Kinases","volume":"293","author":"Wilson","year":"2001","journal-title":"Science"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"6379","DOI":"10.1172\/JCI94171","article-title":"Mutation Affecting the Conserved Acidic WNK1 Motif Causes Inherited Hyperkalemic Hyperchloremic Acidosis","volume":"130","author":"Kouranti","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_91","unstructured":"Prakash, Y.S. (2024). Familial Hyperkalemic Hypertension. Comprehensive Physiology, Wiley."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1007\/s00380-008-1071-8","article-title":"Altered Expression of Na+ Transporters at the mRNA Level in Rat Normal and Hypertrophic Myocardium","volume":"24","author":"Yamamoto","year":"2009","journal-title":"Heart Vessels"},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Linscheid, N., Santos, A., Poulsen, P.C., Mills, R.W., Calloe, K., Leurs, U., Ye, J.Z., Stolte, C., Thomsen, M.B., and Bentzen, B.H. (2021). Quantitative Proteome Comparison of Human Hearts with Those of Model Organisms. PLoS Biol., 19.","DOI":"10.1371\/journal.pbio.3001144"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1260419","DOI":"10.1126\/science.1260419","article-title":"Tissue-Based Map of the Human Proteome","volume":"347","author":"Fagerberg","year":"2015","journal-title":"Science"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"eaay5947","DOI":"10.1126\/science.aay5947","article-title":"An Atlas of the Protein-Coding Genes in the Human, Pig, and Mouse Brain","volume":"367","author":"Zhong","year":"2020","journal-title":"Science"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1038\/s41586-020-2797-4","article-title":"Cells of the Adult Human Heart","volume":"588","author":"Maatz","year":"2020","journal-title":"Nature"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1007\/s00395-006-0604-5","article-title":"Increased Expression and Function of the Myocardial Na\u2013K\u20132Cl Cotransporter in Failing Rat Hearts","volume":"101","author":"Andersen","year":"2006","journal-title":"Basic Res. Cardiol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"H515","DOI":"10.1152\/ajpheart.2001.281.2.H515","article-title":"Protection of Ischemic Myocardium in Diabetics by Inhibition of Electroneutral Na+-K+-2Cl\u2212 Cotransporter","volume":"281","author":"Ramasamy","year":"2001","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1159\/000430392","article-title":"Role of Na+-K+-2Cl\u2212 Cotransporter 1 in Phenylephrine-Induced Rhythmic Contraction in the Mouse Aorta: Regulation of Na+-K+-2Cl\u2212 Cotransporter 1 by Ca2+ Sparks and KCa Channels","volume":"37","author":"Shen","year":"2015","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1038\/hr.2012.37","article-title":"Upregulation of the Na+-K+-2Cl\u2212 Cotransporter 1 via Histone Modification in the Aortas of Angiotensin II-Induced Hypertensive Rats","volume":"35","author":"Cho","year":"2012","journal-title":"Hypertens. Res."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"C608","DOI":"10.1152\/ajpcell.1996.270.2.C608","article-title":"Effects of Na-K-2Cl Cotransport Inhibition on Myocardial Na and Ca during Ischemia and Reperfusion","volume":"270","author":"Anderson","year":"1996","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1111\/j.1748-1716.2010.02099.x","article-title":"Localization and Functional Characterization of the Human NKCC2 Isoforms","volume":"199","author":"Carota","year":"2010","journal-title":"Acta Physiol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/s00424-008-0607-1","article-title":"Thick Ascending Limb: The Na+:K+:2Cl\u2212 Co-Transporter, NKCC2, and the Calcium-Sensing Receptor, CaSR","volume":"458","author":"Gamba","year":"2009","journal-title":"Pfl\u00fcg. Arch.-Eur. J. Physiol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"F192","DOI":"10.1152\/ajprenal.00258.2012","article-title":"Going with the Flow: Regulation of the Thick Ascending Limb","volume":"303","author":"Ferreri","year":"2012","journal-title":"Am. J. Physiol.-Ren. Physiol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1097\/MNH.0000000000000531","article-title":"Molecular Regulation of NKCC2 in Blood Pressure Control and Hypertension","volume":"28","author":"Caceres","year":"2019","journal-title":"Curr. Opin. Nephrol. Hypertens."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1038\/ki.1996.300","article-title":"Localization of the Thiazide Sensitive Na-Cl Cotransporter, rTSC1, in the Rat Kidney","volume":"50","author":"Plotkin","year":"1996","journal-title":"Kidney Int."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1159\/000129627","article-title":"Lithium Fluxes Indicate Presence of Na-Cl Cotransport (NCC) in Human Lens Epithelial Cells","volume":"21","author":"Lauf","year":"2008","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"2015","DOI":"10.1016\/S0006-3495(95)80378-4","article-title":"Rate of Diastolic Ca Release from the Sarcoplasmic Reticulum of Intact Rabbit and Rat Ventricular Myocytes","volume":"68","author":"Bassani","year":"1995","journal-title":"Biophys. J."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"2509","DOI":"10.1681\/ASN.2007030348","article-title":"Thiazide Diuretics Directly Induce Osteoblast Differentiation and Mineralized Nodule Formation by Interacting with a Sodium Chloride Co-Transporter in Bone","volume":"18","author":"Dvorak","year":"2007","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1006\/bbrc.1996.0893","article-title":"Identification of a cDNA Encoding a Thiazide-Sensitive Sodium-Chloride Cotransporter from the Human and Its mRNA Expression in Various Tissues","volume":"223","author":"Chang","year":"1996","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"2749","DOI":"10.1073\/pnas.90.7.2749","article-title":"Primary Structure and Functional Expression of a cDNA Encoding the Thiazide-Sensitive, Electroneutral Sodium-Chloride Cotransporter","volume":"90","author":"Gamba","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"Uchida, S., Mori, T., Susa, K., and Sohara, E. (2023). NCC Regulation by WNK Signal Cascade. Front. Physiol., 13.","DOI":"10.3389\/fphys.2022.1081261"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1097\/MNH.0000000000000910","article-title":"Role of NCC in the Pathophysiology of Hypertension in Primary Aldosteronism","volume":"32","year":"2023","journal-title":"Curr. Opin. Nephrol. Hypertens."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1016\/j.apsb.2020.09.009","article-title":"Regulatory Control of the Na\u2013Cl Co-Transporter NCC and Its Therapeutic Potential for Hypertension","volume":"11","author":"Koeners","year":"2021","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"30570","DOI":"10.1074\/jbc.M705095200","article-title":"A Novel N-Terminal Isoform of the Neuron-Specific K-Cl Cotransporter KCC2","volume":"282","author":"Uvarov","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1002\/cne.23510","article-title":"Distribution of Neuronal KCC2a and KCC2b Isoforms in Mouse CNS","volume":"522","author":"Markkanen","year":"2014","journal-title":"J. Comp. Neurol."},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Ludwig, A., Rivera, C., and Uvarov, P. (2017). A Noninvasive Optical Approach for Assessing Chloride Extrusion Activity of the K\u2013Cl Cotransporter KCC2 in Neuronal Cells. BMC Neurosci., 18.","DOI":"10.1186\/s12868-017-0336-5"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"F1246","DOI":"10.1152\/ajprenal.00464.2004","article-title":"NH2-Terminal Heterogeneity in the KCC3 K+-Cl\u2212 Cotransporter","volume":"289","author":"Mercado","year":"2005","journal-title":"Am. J. Physiol.-Ren. Physiol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1161\/01.RES.0000204449.83861.22","article-title":"Neurogenic Mechanisms Contribute to Hypertension in Mice with Disruption of the K-Cl Cotransporter KCC3","volume":"98","author":"Rust","year":"2006","journal-title":"Circ. Res."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"5422","DOI":"10.1093\/emboj\/cdg519","article-title":"Loss of K-Cl Co-transporter KCC3 Causes Deafness, Neurodegeneration and Reduced Seizure Threshold","volume":"22","author":"Boettger","year":"2003","journal-title":"EMBO J."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1007\/0-387-23752-6_35","article-title":"Hypertension in K-Cl Cotransporter-3 Knockout Mice","volume":"Volume 559","author":"Lauf","year":"2005","journal-title":"Cell Volume and Signaling"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"30326","DOI":"10.1074\/jbc.M003112200","article-title":"Functional Comparison of the K+-Cl\u2212 Cotransporters KCC1 and KCC4","volume":"275","author":"Mercado","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"3154","DOI":"10.1016\/j.bbagen.2017.09.007","article-title":"Molecular Features and Physiological Roles of K+-Cl\u2212 Cotransporter 4 (KCC4)","volume":"1861","author":"Marcoux","year":"2017","journal-title":"Biochim. Biophys. Acta (BBA) -Gen. Subj."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"9760","DOI":"10.1074\/jbc.274.14.9760","article-title":"Both Gs and Gi Proteins Are Critically Involved in Isoproterenol-Induced Cardiomyocyte Hypertrophy","volume":"274","author":"Zou","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1038\/16697","article-title":"The K+\/Cl\u2212 Co-Transporter KCC2 Renders GABA Hyperpolarizing during Neuronal Maturation","volume":"397","author":"Rivera","year":"1999","journal-title":"Nature"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/S0896-6273(01)00297-5","article-title":"Disruption of KCC2 Reveals an Essential Role of K-Cl Cotransport Already in Early Synaptic Inhibition","volume":"30","author":"Stein","year":"2001","journal-title":"Neuron"},{"key":"ref_127","first-page":"E879","article-title":"Phosphorylation by PKC and PKA Regulate the Kinase Activity and Downstream Signaling of WNK4","volume":"114","author":"Arroyo","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1681\/ASN.20223311S1136d","article-title":"PKA Regulates the WNK-SPAK-NCC\/NKCC2 Signaling Pathway Through Phosphorylation of WNK4 and I-1: TH-PO318","volume":"33","author":"Bourqui","year":"2022","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"75","DOI":"10.31857\/S0301179824040041","article-title":"Chloride Channels and Transporters\u2014Role in the Electrical Activity of Pacemaker and Working Myocardium","volume":"55","author":"Voronina","year":"2024","journal-title":"Usp. Fiziol. Nauk."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"RA161","DOI":"10.12659\/MSM.883533","article-title":"The Na+\/Ca2+ Exchanger in Cardiac Ischemia\/Reperfusion Injury","volume":"18","author":"Chen","year":"2012","journal-title":"Med. Sci. Monit."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1161\/01.RES.0000181170.87738.f3","article-title":"Calpain-Mediated Impairment of Na+\/K+\u2013ATPase Activity During Early Reperfusion Contributes to Cell Death After Myocardial Ischemia","volume":"97","author":"Inserte","year":"2005","journal-title":"Circ. Res."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"1956","DOI":"10.1161\/CIRCRESAHA.116.304678","article-title":"Role of Sodium and Calcium Dysregulation in Tachyarrhythmias in Sudden Cardiac Death","volume":"116","author":"Wagner","year":"2015","journal-title":"Circ. Res."},{"key":"ref_133","doi-asserted-by":"crossref","unstructured":"Wang, C., Huang, X., Zhang, Z., Lin, D., and Huang, S. (2026). The Exquisite Link between Potassium Homeostasis Regulation and Cardiovascular Health: Exploration and Analysis. Front. Physiol., 17.","DOI":"10.3389\/fphys.2026.1772535"},{"key":"ref_134","doi-asserted-by":"crossref","unstructured":"Tang, X. (2020). Neuronal Chloride Transporters in Health and Disease, Elsevier Science & Technology.","DOI":"10.1016\/B978-0-12-815318-5.00023-6"},{"key":"ref_135","doi-asserted-by":"crossref","unstructured":"O\u2019Malley, H.A., and Isom, L.L. (2020). The Role of Cation-Chloride Co-Transporters in Cardiovascular and Respiratory Abnormalities and SUDEP. Neuronal Chloride Transporters in Health and Disease, Elsevier.","DOI":"10.1016\/B978-0-12-815318-5.00015-7"},{"key":"ref_136","doi-asserted-by":"crossref","unstructured":"Juricic, S., Klac, J., Stojkovic, S., Beleslin, B., Tesic, M., Jovanovic, I., Banovic, M., Petrovic, O., Aleksandric, S., and Vasic, N. (2026). Molecular and Cellular Mechanisms of Myocardial Ischemia and Reperfusion Injury: A Narrative Review. Cells, 15.","DOI":"10.3390\/cells15030265"},{"key":"ref_137","doi-asserted-by":"crossref","unstructured":"Wang, R., Wang, M., He, S., Sun, G., and Sun, X. (2020). Targeting Calcium Homeostasis in Myocardial Ischemia\/Reperfusion Injury: An Overview of Regulatory Mechanisms and Therapeutic Reagents. Front. Pharmacol., 11.","DOI":"10.3389\/fphar.2020.00872"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"3084","DOI":"10.1002\/ejhf.70081","article-title":"The Chloride Paradigm Shift in Heart Failure: From Neglected Ion to Keystone of Precision Diuretic Therapy","volume":"27","author":"Domingo","year":"2025","journal-title":"Eur. J. Heart Fail."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1007\/s40119-021-00238-2","article-title":"Chloride in Heart Failure Syndrome: Its Pathophysiologic Role and Therapeutic Implication","volume":"10","author":"Kataoka","year":"2021","journal-title":"Cardiol. Ther."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"C1191","DOI":"10.1152\/ajpcell.00259.2013","article-title":"Enhanced Cell Volume Regulation: A Key Mechanism in Local and Remote Ischemic Preconditioning","volume":"306","author":"Diaz","year":"2014","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"103624","DOI":"10.1016\/j.isci.2021.103624","article-title":"Beat-to-Beat Dynamic Regulation of Intracellular pH in Cardiomyocytes","volume":"25","author":"Lyu","year":"2022","journal-title":"iScience"},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"2953","DOI":"10.3892\/mmr.2017.6882","article-title":"Sasanquasaponin Induces Increase of Cl\u2212\/HCO3\u2212 Exchange of Anion Exchanger 3 and Promotes Intracellular Cl\u2212 Efflux in Hypoxia\/Reoxygenation Cardiomyocytes","volume":"16","author":"Qiu","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1007\/s11010-011-0855-9","article-title":"Mechanisms of Chloride in Cardiomyocyte Anoxia-Reoxygenation Injury: The Involvement of Oxidative Stress and NF-kappaB Activation","volume":"355","author":"Liu","year":"2011","journal-title":"Mol. Cell. Biochem."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"BSR20240029","DOI":"10.1042\/BSR20240029","article-title":"Chloride Ions in Health and Disease","volume":"44","author":"Raut","year":"2024","journal-title":"Biosci. Rep."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"102117","DOI":"10.1016\/j.cpcardiol.2023.102117","article-title":"LOX-1 Receptor: A Diagnostic Tool and Therapeutic Target in Atherogenesis","volume":"49","author":"Pyrpyris","year":"2024","journal-title":"Curr. Probl. Cardiol."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"C674","DOI":"10.1152\/ajpcell.00312.2002","article-title":"Platelet-Derived Growth Factor Regulates K-Cl Cotransport in Vascular Smooth Muscle Cells","volume":"284","author":"Zhang","year":"2003","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"ref_147","doi-asserted-by":"crossref","unstructured":"Fu, Y., Zhao, D., Zhou, Y., Lu, J., Kang, L., Jiang, X., Xu, R., Ding, Z., and Zou, Y. (2022). Identification of Differential Expression Genes between Volume and Pressure Overloaded Hearts Based on Bioinformatics Analysis. Genes, 13.","DOI":"10.3390\/genes13071276"},{"key":"ref_148","first-page":"140","article-title":"Wnk1-Osr1\/Spak kinase cascade is important for angiogenesis","volume":"131","author":"Huang","year":"2020","journal-title":"Trans. Am. Clin. Climatol. Assoc."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"e2203743119","DOI":"10.1073\/pnas.2203743119","article-title":"WNK1 Collaborates with TGF-\u03b2 in Endothelial Cell Junction Turnover and Angiogenesis","volume":"119","author":"Jaykumar","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"15999","DOI":"10.1073\/pnas.1419057111","article-title":"Actions of the Protein Kinase WNK1 on Endothelial Cells Are Differentially Mediated by Its Substrate Kinases OSR1 and SPAK","volume":"111","author":"Dbouk","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1097\/MNH.0000000000000820","article-title":"WNK1 in the Kidney","volume":"31","author":"Gamba","year":"2022","journal-title":"Curr. Opin. Nephrol. Hypertens."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"14366","DOI":"10.1073\/pnas.1304230110","article-title":"WNK1 -Related Familial Hyperkalemic Hypertension Results from an Increased Expression of L-WNK1 Specifically in the Distal Nephron","volume":"110","author":"Mutig","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1007\/s10157-012-0590-x","article-title":"Effect of Heterozygous Deletion of WNK1 on the WNK-OSR1\/SPAK-NCC\/NKCC1\/NKCC2 Signal Cascade in the Kidney and Blood Vessels","volume":"16","author":"Susa","year":"2012","journal-title":"Clin. Exp. Nephrol."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1161\/HYPERTENSIONAHA.111.172429","article-title":"WNK1 Regulates Vasoconstriction and Blood Pressure Response to \u03b11 -Adrenergic Stimulation in Mice","volume":"58","author":"Bergaya","year":"2011","journal-title":"Hypertension"},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"e2322135121","DOI":"10.1073\/pnas.2322135121","article-title":"WNK Kinase Is a Vasoactive Chloride Sensor in Endothelial Cells","volume":"121","author":"Garrud","year":"2024","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/bs.ctdb.2016.08.004","article-title":"WNK Kinases in Development and Disease","volume":"Volume 123","author":"Rodan","year":"2017","journal-title":"Current Topics in Developmental Biology"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1681\/ASN.2014070639","article-title":"Kelch-Like Protein 2 Mediates Angiotensin II\u2013With No Lysine 3 Signaling in the Regulation of Vascular Tonus","volume":"26","author":"Zeniya","year":"2015","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1161\/HYPERTENSIONAHA.113.01543","article-title":"Dietary Salt Intake Regulates WNK3\u2013SPAK\u2013NKCC1 Phosphorylation Cascade in Mouse Aorta Through Angiotensin II","volume":"62","author":"Zeniya","year":"2013","journal-title":"Hypertension"},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1152\/physrev.00044.2018","article-title":"Regulation of the Renal NaCl Cotransporter and Its Role in Potassium Homeostasis","volume":"100","author":"Hoorn","year":"2020","journal-title":"Physiol. Rev."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1161\/01.RES.88.2.132","article-title":"Potassium Ions as Vasodilators: Role of Inward Rectifier Potassium Channels","volume":"88","author":"Eckman","year":"2001","journal-title":"Circ. Res."},{"key":"ref_161","first-page":"35","article-title":"High Potassium Concentration Regulates the WNK3\u2013SPAK\u2013NKCC1 Phosphorylation Cascade via Kelch-like Protein 2 in Mouse Vascular Smooth Muscle Cells","volume":"65","author":"Wang","year":"2018","journal-title":"J. Med. Dent. Sci."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1080\/14728222.2017.1351949","article-title":"Pharmacological Targeting of SPAK Kinase in Disorders of Impaired Epithelial Transport","volume":"21","author":"Zhang","year":"2017","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"4545","DOI":"10.1093\/hmg\/ddv185","article-title":"Critical Role of the SPAK Protein Kinase CCT Domain in Controlling Blood Pressure","volume":"24","author":"Zhang","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"EMBR202050766","DOI":"10.15252\/embr.202050766","article-title":"SIRT7 Modulates the Stability and Activity of the Renal K-Cl Cotransporter KCC4 through Deacetylation","volume":"22","author":"Noriega","year":"2021","journal-title":"EMBO Rep."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1016\/j.trechm.2021.05.004","article-title":"Cation-Coupled Chloride Cotransporters: Chemical Insights and Disease Implications","volume":"3","author":"Portioli","year":"2021","journal-title":"Trends Chem."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"3885","DOI":"10.1093\/hmg\/ddq303","article-title":"Genome-Wide Association Analysis Identifies Multiple Loci Related to Resting Heart Rate","volume":"19","author":"Eijgelsheim","year":"2010","journal-title":"Hum. Mol. Genet."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/17\/1549\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T02:24:15Z","timestamp":1788143055000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/17\/1549"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,27]]},"references-count":166,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["cells15171549"],"URL":"https:\/\/doi.org\/10.3390\/cells15171549","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,27]]}}}