Clinical data indicate that a low potassium intake aggravates hypertension, particularly when sodium intake is high. Recent studies suggest that this influence may be mediated by the action of WNK and SPAK kinases which modulate the responsiveness of the distal nephron. In the present study we therefore analyzed the effect of reducing potassium intake on the expression of WNK and SPAK kinases in the nephron. Mice were fed a high sodium (3%) diet containing either normal (0.93%) or low (0.03%) potassium for 10 days. Telemetric mean arterial blood pressure (MAP) significantly increased in the low potassium but remained unaffected in the normal potassium group. Renal Na⁺ clearance was reduced to ~65% after 10 days of low potassium intake as compared to the normal potassium diet. Real time PCR analysis in the whole kidney, convoluted tubules (DCT), and cortical collecting ducts (CCD) revealed a significantly increased expression of WNK4, SPAK, and NCC expression after 10 days of low vs. normal potassium intake. To investigate a possible involvement of angiotensin II in this altered expression, mice were treated with the selectice angiotensin AT1 receptor antagonist losartan (30 mg/kg/day). AT1 receptor blockade completely normalized MAP and significantly reduced the activation of WNK4 mRNA expression. These data demonstrate that potassium depletion causes sodium retention and an elevation of blood pressure in sodium replete mice. These changes were accompanied by a molecular remodeling of the distal nephron consistent with an activation the NCC by the WNK4-SPAK-pathway by AT1 receptors.