Mutations in the gene encoding the serine-threonine kinase WNK1 are responsible for Familial Hyperkalemic Hypertension (FHHt), a rare form of hypertension associated with hyperkaliemia and hyperchloremic metabolic acidosis. WNK1 gives rise to a ubiquitous isoform, L-WNK1, and a kinase-deficient isoform expressed exclusively in the nephron, KS-WNK1. Several other isoforms are generated through alternative splicing although this has never been studied in detail. We first established an exhaustive description of all WNK1 isoforms and quantified their relative level of expression in a panel of human and mouse tissues and in mouse nephron segments. We thus showed that 9 exons of WNK1 are alternatively spliced in a tissue-specific manner. In a second part of the work, in order to elucidate the mechanisms underlying FHHt pathogenesis and thereby the role of WNK1 in ion homeostasis and blood pressure, we generated WNK1+/FHHt mice harbouring a deletion of WNK1 first intron, i.e. the human FFHt mutation. These mice display increased blood pressure, hyperkalemia and hyperchloremic metabolic acidosis. We demonstrated that this phenotype results from an activation of the sodium-chloride co-transporteur NCC induced by the overexpression of L-WNK1 in the distal nephron.In conclusion, this work provided a detailed description of all WNK1 isoforms and their pattern of expression and allowed a better understanding of the pathophysiology of WNK1-related FHHt
From the deletion of WNK1 first intron to hypertension : characterization of a mouse model of Familial Hyperkalemic Hypertension, a monogenic form of hypertension