Clinical data indicate that a high dietary K⁺ intake attenuates the development of salt-sensitive hypertension. Recent studies suggest that this influence of the K⁺ diet on blood pressure may be mediated by the action of WNK kinases which modulate the responsiveness of the distal nephron to aldosterone, so that K⁺ excretion is favoured at the expense of Na⁺ retention. To investigate, whether this mechanism is also effective in the presence of a high salt intake, which suppresses aldosterone levels, we fed C57bl6 mice a high Na⁺ intake (3%Na⁺) combined with either a low K⁺ (0.03%), an intermediate K⁺ (0.93%), or a high K⁺ (5%) diet for 10 days. Mean arterial blood pressure, measured by telemetry, was significantly higher during the activity period in animals receiving either the low K⁺ (D5.5±1.5 mmHg) or the high K⁺ (D15.7±3.3 mmHg) diet than in mice on the intermediate K⁺ diet. In parallel, Na⁺ clearance was reduced to ~65% during both low K⁺ (10.5±0.9ml/24h) and high K⁺ intake (10.5±0.9ml/24h) as compared to the intermediate K⁺ diet (15.7±1.6ml/24h). Analysis of the mRNA expression by real time PCR in the whole kidney and in microdissected nephron segments (distal convoluted tubules, DCT, and cortical collecting duct, CCD) revealed a significantly increased expression of WNK4 and NCC during the low K⁺ diet. In contrast, during high K⁺ intake a significant increase of SGK1, ENaCß, and the KS-WNK1/L-WNK1 ratio was found. These data demonstrate that dietary K⁺ restriction as well as dietary K⁺ excess can increase MAP and promote Na⁺ retention in mice concurrently receiving a high Na⁺ intake. The gene expression data suggest that these effects are mediated by two distinct mechanisms, i.e. activation of WNK4 and NCC during K⁺ restriction, and activation of SGK1 and ENaCß during K⁺ excess.