Low dietary potassium intake stimulates NCC to cause sodium retention (892.16)

Low dietary K+ stimulates the renal sodium chloride cotransporter (NCC), whereas high salt intake inhibits it. As most people in the world consume a diet that is both low in K+ and high in salt, we investigated how NCC responds to conflicting Na+ and K+ signals. High salt (HS)/ low K+ (LK) intake increased NCC and pNCC compared with HS/normal K+ (NK) and redistributed SPAK, OSR1, and WNK4 to cytoplasmic punctae. These effects were preserved in both SPAK‐/‐ and AT1aR‐/‐ mice. A HS/LK diet also decreased urinary Na+, compared with a HS/NK diet. This anti‐natriuretic effect, however was absent in NCC‐/‐ mice. As mineralocorticoids have been reported to stimulate NCC, we confirmed that fludrocortisone (F) increases NCC and phosphorylated NCC (pNCC) in mice. A high K+ diet, which normalized plasma K+, prevented the effects of F on pNCC. F also caused substantially more hypokalemia in NCC‐/‐ mice, than in wild type mice, suggesting that NCC is essential to preserve plasma K+. Amiloride, which caused hyperkalemia and volume contraction, decreased NCC and pNCC, suggesting K+ was determining NCC status. Mice treated with both F and A had plasma K+ and both NCC and pNCC levels equal to A alone. In HEK293 cells, low K+ medium increased pNCC and pSPAK/pOSR1, an effect that was dependent on WNK kinases as shown through siRNA studies. Transfection with mutant KCNJ10 channels that depolarize cells, including multiple EAST sydrome mutants, reduced pNCC compared with wild type KCNJ10. Treatment with barium also reduced pNCC. The results suggest that low plasma K+ stimulates NCC directly, independent of any intermediating signaling hormones; this effect likely requires WNK‐SPAK/OSR1. Our data suggest that the DCT responds to plasma K+ and predominantly modulates renal K+ excretion. Grant Funding Source : Supported by NIDDK, the Department of Veterans Affairs, and the American Heart Association