The actual target of CN may be KLHL3 because KLHL3 phosphorylation was higher in cells treated with tacrolimus and in mice with tacrolimus-induced hypertension.93 As noted above, KLHL3 phosphorylation impairs WNK4 binding to CUL3-KLHL3, preventing WNK4 ubiquitination and subsequent proteasomal degradation, enhancing WNK-SPAK/OSR1-mediated NCC phosphorylation. This evidence concerns the gene CUL3 and hypertensive disorder.