WNK bodies cluster WNK4 and SPAK/OSR1 to promote NCC activation in hypokalemia - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue American Journal of Physiology. Renal Physiology Année : 2020

WNK bodies cluster WNK4 and SPAK/OSR1 to promote NCC activation in hypokalemia

Résumé

K + deficiency stimulates renal salt reuptake via the Na + -Cl − cotransporter (NCC) of the distal convoluted tubule (DCT), thereby reducing K + losses in downstream nephron segments while increasing NaCl retention and blood pressure. NCC activation is mediated by a kinase cascade involving with no lysine (WNK) kinases upstream of Ste20-related proline-alanine-rich kinase (SPAK) and oxidative stress-responsive kinase-1 (OSR1). In K + deficiency, WNKs and SPAK/OSR1 concentrate in spherical cytoplasmic domains in the DCT termed “WNK bodies,” the significance of which is undetermined. By feeding diets of varying salt and K + content to mice and using genetically engineered mouse lines, we aimed to clarify whether WNK bodies contribute to WNK-SPAK/OSR1-NCC signaling. Phosphorylated SPAK/OSR1 was present both at the apical membrane and in WNK bodies within 12 h of dietary K + deprivation, and it was promptly suppressed by K + loading. In WNK4-deficient mice, however, larger WNK bodies formed, containing unphosphorylated WNK1, SPAK, and OSR1. This suggests that WNK4 is the primary active WNK isoform in WNK bodies and catalyzes SPAK/OSR1 phosphorylation therein. We further examined mice carrying a kidney-specific deletion of the basolateral K + channel-forming protein Kir4.1, which is required for the DCT to sense plasma K + concentration. These mice displayed remnant mosaic expression of Kir4.1 in the DCT, and upon K + deprivation, WNK bodies developed only in Kir4.1-expressing cells. We postulate a model of DCT function in which NCC activity is modulated by plasma K + concentration via WNK4-SPAK/OSR1 interactions within WNK bodies.

Dates et versions

hal-03832892 , version 1 (28-10-2022)

Identifiants

Citer

Martin N Thomson, Catherina A Cuevas, Tim M Bewarder, Carsten Dittmayer, Lauren N Miller, et al.. WNK bodies cluster WNK4 and SPAK/OSR1 to promote NCC activation in hypokalemia. American Journal of Physiology. Renal Physiology, 2020, 318 (1), pp.F216-F228. ⟨10.1152/ajprenal.00232.2019⟩. ⟨hal-03832892⟩
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