Kidney-specific WNK1 isoform (KS-WNK1) is a potent activator of WNK4 and NCC.

Kidney-specific WNK1 isoform (KS-WNK1) is a potent activator of WNK4 and NCC. Am J Physiol Renal Physiol. 2018 May 30;: Authors: Argaiz ER, Chavez-Canales M, Ostrosky-Frid M, Rodriguez-Gama A, Vázquez N, Gonzalez-Rodriguez X, Garcia-Valdés J, Hadchouel J, Ellison DH, Gamba G Abstract Familial Hyperkalemic Hypertension (FHHt) can be mainly attributed to increased activity of the renal Na+:Cl- cotransporter (NCC), which is caused by altered expression and regulation of the WNK1 and WNK4 kinases. The WNK1 gene gives rise to a kidney-specific isoform that lacks the kinase domain (KS-WNK1), the expression of which occurs primarily in the distal convoluted tubule. The role played by KS-WNK1 in the modulation of the WNK/SPAK/NCC pathway remains elusive. In the present study, we assessed the effect of human KS-WNK1 on NCC activity and on the WNK4-SPAK pathway. Microinjection of oocytes with human KS-WNK1 cRNA induces remarkable activation and phosphorylation of SPAK and NCC. The effect of KS-WNK1 was abrogated by eliminating a WNK-WNK interacting domain and by a specific WNK inhibitor, WNK463, indicating that the activation of SPAK/NCC by KS-WNK1 is due to interaction with another WNK kinase. Under control conditions in oocytes, the activating serine 335 of the WNK4 T loop is not phosphorylated. In contrast, this serine becomes phosphorylated when the intracellular chloride concentration ([Cl-]i) is reduced or when KS-WNK1 is co-expressed with WNK4...
Source: Am J Physiol Renal P... - Category: Urology & Nephrology Authors: Tags: Am J Physiol Renal Physiol Source Type: research

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