Fig. 4. Proposed mechanism by which the WNK-SPAK/OSR1 signalling pathway regulates salt re-absorption and blood pressure. Although there is clear evidence that WNK1 activates NCC via SPAK and OSR1, further work is required to determine whether other WNK isoforms regulate ion co-transporters through SPAK and OSR1. It should also be noted that most studies that employ overexpression systems have reported that WNK4 negatively regulates NCC. Whether this inhibitory effect is mediated through SPAK or OSR1 has not been studied.