Wnk4, or With no lysine kinase-4, belongs to a serine-threonine kinase family characterized by an atypical lysine position in its catalytic domain. It is crucial for maintaining body sodium and potassium homeostasis, mainly acting as a positive regulator of the thiazide-sensitive NaCl cotransporter (NCC) in the distal convoluted tubule of the nephron [1]. It is also involved in the Ste20/SPS1-related proline-alanine-rich kinase/oxidative stress responsive kinase-1-NCC pathway, which impacts salt reabsorption and renal K+ secretion [1]. Genetically modified mouse models have been instrumental in studying its functions [1].

In Wnk4 knockout (WNK4-/-) mice, several phenotypes have been observed. After acute furosemide treatment, WNK4-/-animals showed increased calcium wasting compared to wild-type controls, with decreased TRPV5 expression along DCT2, indicating that Wnk4 limits distal calcium losses through regulating TRPV5 [3]. Wnk4 or SpaK knockout in mice suppressed p-NKCC1 expression and inflammation cascade activation in alveolar macrophages, attenuating LPS-induced alveolar cell-population shifting, macrophage NKCC1 phosphorylation, and acute lung injury, suggesting that the Wnk4-SpaK-NKCC1 cascade modulates macrophage activation [2]. In lipopolysaccharide (LPS)-induced acute respiratory distress syndrome (ARDS) mouse models, gene-silencing of Wnk4 by siRNA transfection in primary rat alveolar epithelial type II (ATII) cells reduced ENaC expression and the level of Wnk4-associated SpaK phosphorylation, showing that the Wnk4/SpaK pathway improves alveolar fluid clearance by upregulating ENaC [4].

In conclusion, through model-based research, Wnk4 has been shown to play essential roles in renal ion transport, calcium homeostasis, macrophage activation, and alveolar fluid clearance. The use of Wnk4 KO mouse models has provided valuable insights into its functions in these biological processes and related disease conditions such as familial hyperkalemic hypertension, acute lung injury, and ARDS [1,2,3,4].

References:

1. Murillo-de-Ozores, Adrián Rafael, Rodríguez-Gama, Alejandro, Carbajal-Contreras, Héctor, Gamba, Gerardo, Castañeda-Bueno, María. 2021. WNK4 kinase: from structure to physiology. In American journal of physiology. Renal physiology, 320, F378-F403. doi:10.1152/ajprenal.00634.2020. https://pubmed.ncbi.nlm.nih.gov/33491560/

2. Hung, Chin-Mao, Peng, Chung-Kan, Yang, Sung-Sen, Shui, Hao-Ai, Huang, Kun-Lun. 2019. WNK4-SPAK modulates lipopolysaccharide-induced macrophage activation. In Biochemical pharmacology, 171, 113738. doi:10.1016/j.bcp.2019.113738. https://pubmed.ncbi.nlm.nih.gov/31786261/

3. Ferdaus, Mohammed Z, Gratreak, Brittany D K, Miller, Lauren, Ellison, David H, Terker, Andrew S. . WNK4 limits distal calcium losses following acute furosemide treatment. In Physiological reports, 7, e14195. doi:10.14814/phy2.14195. https://pubmed.ncbi.nlm.nih.gov/31496133/

4. Deng, Wang, Qi, Di, Tang, Xu-Mao, He, Jing, Wang, Dao-Xin. . THE WNK4/SPAK PATHWAY STIMULATES ALVEOLAR FLUID CLEARANCE BY UPREGULATION OF EPITHELIAL SODIUM CHANNEL IN MICE WITH LIPOPOLYSACCHARIDE-INDUCED ACUTE RESPIRATORY DISTRESS SYNDROME. In Shock (Augusta, Ga.), 58, 68-77. doi:10.1097/SHK.0000000000001945. https://pubmed.ncbi.nlm.nih.gov/35670456/