The WNK/SPAK "potassium-switch" pathway provides a homeostatic mechanism that activates the sodium chloride cotransporter, NCC, to limit urinary potassium excretion in dietary potassium deficiency at the expense of increasing salt-sensitivity and blood pressure. While it is well established that high dietary potassium turns off this switch and suppresses NCC activity, several studies suggest that the counter-anion accompanying potassium may modify this response. The goal of this study was to determine whether the chronic response to high dietary potassium depends on the K + counter-anion. Wild-type mice were fed either control (1% K + ), high KCl (5% K + ), high KHCO 3 (5% K + ), or physiologic high-potassium diets (2% K + ) formulated with either chloride or bicarbonate as the counter-anion. Physiological, molecular, and imaging analyses were performed to examine NCC activity and the WNK/SPAK pathway. To specifically test whether bicarbonate alone can activate the pathway, WT mice were also given NaHCO 3 in drinking water for 7 days. We found chronic KHCO 3 intake significantly increases NCC phosphorylation in WT mice, an effect driven by enhanced WNK-SPAK signaling. In the kidney cortex, both total SPAK and phospho-SPAK (Ser373) were markedly elevated in KHCO 3 -fed mice compared with control and KCl-fed groups. WNK bodies, identified as WNK4-positive molecular condensates in NCC-expressing segments, were more numerous and larger in KHCO 3 -fed mice than in the other groups. Importantly, activation of NCC and the Switch Pathway also occurred when KHCO 3 was provided at physiological potassium levels, underscoring the translational relevance of this regulation. Metabolic cage studies further revealed that KHCO 3 -induced NCC activation was functionally associated with reduced natriuresis, reflected by a marked decrease in 24-hour urinary sodium excretion. The inhibited natriuresis was accompanied by polydipsia and polyuria. To understand the physiologic relevance of increased NCC under chronic KHCO 3 intake, we analyzed salt transporters in the upstream nephron segment, namely NHE3 and NKCC2. While NKCC2 level was unchanged, NHE3 was strongly suppressed by chronic KHCO 3 intake, suggesting that the activation of distal Na + reabsorption is required to maintain Na + homeostasis, as NHE3 function is reduced due to alkalosis To isolate the specific role of bicarbonate, we examined NCC and the switch pathway after 7 days of NaHCO 3 treatment. This intervention strongly increased SPAK and NCC phosphorylation, demonstrating that HCO 3 - alone, independent of its accompanying cation, is sufficient to activate the Switch Pathway. In summary, our findings demonstrate that bicarbonate loading activates the Switch Pathway and distal Na + reabsorption even in the context of high potassium intake, most likely to prevent renal Na + loss. Because HCO 3 - treatment also causes hypochloremia, the observed pathway activation may be driven by elevated plasma HCO 3 -/pH, reduced chloride levels, or a combination of both. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Alqusairi et al. (Fri,) studied this question.