Fig. 3.

The “stimulatory” pathway of WNK4. a Activation of WNK4 by angiotensin II potentially occurring via elevations in intracellular Ca²⁺. In this state, WNK4 stimulates the SPAK/OSR1 pathway. Cl⁻-depletion and K⁺-depletion activates WNK1, thereby activating the SPAK and OSR1 kinases. In both cases, activation of the STE20 kinases leads to increased phosphorylation level of NCC. The augmented phosphorylation level of NCC increases cotransport activity. b Potential mechanism whereby gain-of-function mutations in WNK4 causes PHAII. Increased activity of WNK4 due to PHAII mutations increases its stimulatory effect on the SPAK/OSR1 pathway. This enhances phosphorylation of NCC and thereby increases NaCl transport, leading to PHAII. c An increase in the expression of WNK1 stimulates the activation of the SPAK/OSR1 kinases, which subsequently increases the phosphorylation level of NCC