Modulation of NCC activity is essential to adjust K⁺ excretion in the face of changes in dietary K⁺ intake. We used previously characterized genetic mouse models to assess the role of SPAK and WNK4 in the modulation of NCC by K⁺ diets. SPAK knockin and WNK4 knockout mice were placed on normal, low or high K⁺ diets for four days. Low K⁺ diet decreased and high K⁺-citrate diet increased plasma aldosterone levels, but both diets were associated with increased phosphorylation of NCC (pNCC; T44/48/53) and pSPAK/OSR1 (S383/S325). The effect of the low K⁺ diet on SPAK phosphorylation persisted in the WNK4 knockout and SPAK knockin mice, while the effects of angiotensin II on NCC and SPAK were lost in both mouse colonies, suggesting that for NCC activation by angiotensin II integrity of the WNK4/SPAK pathway is required, while for low K⁺ diet SPAK phosphorylation occurred despite the absence of WNK4, suggesting the involvement of another WNK kinase. Additionally, because NCC activation also occurred in SPAK knockin mice, it is possible that loss of SPAK was compensated by OSR1. The positive effect of high K⁺ diet was observed when the accompanying anion was citrate, while high KCl diet reduced NCC phosphorylation. However, the effect of high K⁺-citrated diet was aldosterone-dependent and neither metabolic alkalosis induced by bicarbonate, nor citrate administration in the absence of K⁺ increased NCC phosphorylation, suggesting that it was not due to the citrate-induced metabolic alkalosis. Thus, accompanying anion might modulate the NCC response to high potassium diet.