Wnk1, short for With No lysine (K) kinase 1, is a serine/threonine protein kinase. It participates in ion homeostasis via the WNK-OSR1/SPAK-NKCC cascade and is involved in multiple biological processes. It also plays a role in cancer metastasis, angiogenesis, and endosomal trafficking [2,3,4]. Genetic models, such as knockout mouse models, have been crucial in studying its functions.

In renal function studies, analyses of microdissected mouse nephron segments showed different abundances of long-WNK1 and kidney-specific-WNK1 transcripts. Familial hyperkalaemic hypertension-causative mutations affecting the acidic domain of WNK1 suggest that KS-WNK1 activates the Na+:Cl- cotransporter NCC [1]. In cancer, knockdown of Wnk1 in hepatocellular carcinoma cells inhibited cell proliferation and xenograft tumor growth. Mechanistically, Wnk1 competes with NRF2 for binding with KEAP1, promoting NRF2-mediated antioxidant response [6]. In vascular smooth muscle cells (VSMCs), deletion of L-Wnk1 in mice led to aortitis and a pathogenic pro-inflammatory phenotype [5].

In conclusion, Wnk1 is essential for various biological functions, including ion homeostasis, cell proliferation, and maintaining cellular phenotypes. Studies using KO/CKO mouse models have revealed its roles in diseases such as familial hyperkalaemic hypertension, hepatocellular carcinoma, and aortitis. These findings provide insights into potential therapeutic targets for these diseases.