Wnk4, short for With no lysine kinase-4, belongs to a serine-threonine kinase family. It has a crucial function in the kidney, mainly as a positive regulator of the thiazide-sensitive NaCl cotransporter (NCC) in the distal convoluted tubule of the nephron. It is involved in the Ste20/SPS1-related proline-alanine-rich kinase/oxidative stress responsive kinase-1-NCC pathway, which is essential for salt reabsorption and indirectly impacts renal K+ secretion. Genetically modified mouse models have been vital in studying Wnk4 [1].

In Wnk4 knockout (WNK4-/-) animals, acute treatment with furosemide led to increased calcium wasting compared to wild-type controls, indicating that Wnk4, via regulation of TRPV5, limits distal calcium losses following furosemide treatment. However, Wnk4 deletion did not affect the chronic renal response to dietary calcium depletion [3]. Also, Wnk4 or SPAK knockout in mice suppressed p-NKCC1 expression and inflammation cascade activation in alveolar macrophages, attenuating lipopolysaccharide-induced alveolar cell-population shifting, macrophage NKCC1 phosphorylation, and acute lung injury, showing its role in modulating macrophage activation [2].

In summary, Wnk4 is essential for renal ion transport regulation, including salt and calcium handling, and also plays a role in modulating macrophage activation. Studies using Wnk4 KO mouse models have provided valuable insights into its functions in kidney-related disorders and lung inflammation, helping to understand the underlying mechanisms and potentially leading to new treatment strategies for associated diseases.