Multiple Molecular Mechanisms Are Involved in the Activation of the Kidney Sodium-Chloride Cotransporter by Hypokalemia
Authors
Adrián R. Murillo-de-Ozores, Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, Mexico City; Faculty of Medicine, Universidad Nacional Autónoma de México, Coyoacan, Mexico City.
Héctor Carbajal-Contreras, Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, Mexico City; PECEM, Faculty of Medicine, Universidad Nacional Autónoma de México, Coyoacan, Mexico City, Mexico.
Germán R. Magaña-Ávila, Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, Mexico City; Faculty of Medicine, Universidad Nacional Autónoma de México, Coyoacan, Mexico City.
Raquel Valdés, Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, Mexico City; Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Tlalpan, Mexico City.
Leoneli I. Grajeda-Medina, Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, Mexico City.
Norma Vázquez, Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Tlalpan, Mexico City.
Teresa Zariñán, Red de Apoyo a la Investigación (RAI), Universidad Nacional Autónoma de México (UNAM), Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), Mexico City, Mexico.
Alejandro López-Saavedra, Unidad de Aplicaciones Avanzadas en Microscopía del Instituto Nacional de Cancerología y la Red de Apoyo a la Investigación, Universidad Nacional Autónoma de México, Mexico City, Mexico.
Avika Sharma, Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland, Oregon, USA.
Dao-Hong Lin, Department of Pharmacology, New York Medical College, Valhalla, New York, USA.
Wen-Hui Wang, Department of Pharmacology, New York Medical College, Valhalla, New York, USA.
Eric Delpire, Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
David H. Ellison, Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland, Oregon, USA; Oregon Clinical & Translational Research Institute, Oregon Health & Science University, Portland, Oregon, USA; Renal Section, VA Portland Health Care System, Portland, Oregon, USA.
Gerardo Gamba, Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, Mexico City; PECEM, Faculty of Medicine, Universidad Nacional Autónoma de México, Coyoacan, Mexico City, Mexico; Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Tlalpan, Mexico City.
María Castañeda-Bueno, Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, Mexico City. Electronic address: maria.castanedab@incmnsz.mx.
Journal Title
Kidney International
Publication Date
11-1-2022
Abstract
Low potassium intake activates the kidney sodium-chloride cotransporter (NCC) whose phosphorylation and activity depend on the With-No-Lysine kinase 4 (WNK4) that is inhibited by chloride binding to its kinase domain. Low extracellular potassium activates NCC by decreasing intracellular chloride thereby promoting chloride dissociation from WNK4 where residue L319 of WNK4 participates in chloride coordination. Since the WNK4-L319F mutant is constitutively active and chloride-insensitive in vitro, we generated mice harboring this mutation that displayed slightly increased phosphorylated NCC and mild hyperkalemia when on a 129/sv genetic background. On a low potassium diet, upregulation of phosphorylated NCC was observed, suggesting that in addition to chloride sensing by WNK4, other mechanisms participate which may include modulation of WNK4 activity and degradation by phosphorylation of the RRxS motif in regulatory domains present in WNK4 and KLHL3, respectively. Increased levels of WNK4 and kidney-specific WNK1 and phospho-WNK4-RRxS were observed in wild-type and WNK4 mice on a low potassium diet. Decreased extracellular potassium promoted WNK4-RRxS phosphorylation in vitro and ex vivo as well. These effects might be secondary to intracellular chloride depletion, as reduction of intracellular chloride in HEK293 cells increased phospho-WNK4-RRxS. Phospho-WNK4-RRxS levels were increased in mice lacking the Kir5.1 potassium channel, which presumably have decreased distal convoluted tubule intracellular chloride. Similarly, phospho-KLHL3 was modulated by changes in intracellular chloride in HEK293 cells. Thus, our data suggest that multiple chloride-regulated mechanisms are responsible for NCC upregulation by low extracellular potassium.
Recommended Citation
Murillo-de-Ozores, A. R., Carbajal-Contreras, H., Magaña-Ávila, G. R., Valdés, R., Grajeda-Medina, L. I., Vázquez, N., Zariñán, T., López-Saavedra, A., Sharma, A., Lin, D., Wang, W., Delpire, E., Ellison, D. H., Gamba, G., & Castañeda-Bueno, M.
(2022). Multiple Molecular Mechanisms Are Involved in the Activation of the Kidney Sodium-Chloride Cotransporter by Hypokalemia. Kidney International, 102 (5), 1030-1041.
https://doi.org/10.1016/j.kint.2022.06.027
