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Abstract
Modulation of Na+-Cl− cotransporter (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 Ste20-related proline-alanine-rich kinase (SPAK) and with-no-lysine kinase (WNK)4 in the modulation of NCC by K+ diets. SPAK knockin and WNK4 knockout mice were placed on normal-, low-, or high-K+-citrate diets for 4 days. The low-K+ diet decreased and high-K+ diet increased plasma aldosterone levels, but both diets were associated with increased phosphorylation of NCC (phospho-NCC, Thr44/Thr48/Thr53) and phosphorylation of SPAK/oxidative stress responsive kinase 1 (phospho-SPAK/OSR1, Ser383/Ser325). The effect of the low-K+ diet on SPAK phosphorylation persisted in WNK4 knockout and SPAK knockin mice, whereas the effects of ANG II on NCC and SPAK were lost in both mouse colonies. This suggests that for NCC activation by ANG II, integrity of the WNK4/SPAK pathway is required, whereas for the low-K+ diet, SPAK phosphorylation occurred despite the absence of WNK4, suggesting the involvement of another WNK (WNK1 or WNK3). 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 the high-K+ diet was observed when the accompanying anion was citrate, whereas the high-KCl diet reduced NCC phosphorylation. However, the effect of the high-K+-citrate 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 citrate-induced metabolic alkalosis. Thus, the accompanying anion might modulate the NCC response to the high-K+ diet.
Highlights
RENAL Kϩ EXCRETION is dependent on Kϩ secretion in the distal nephron because the filtered Kϩ is almost completely reabsorbed in the proximal convoluted tubule
Salt reabsorption in the distal convoluted tubule (DCT) occurs through the thiazide-sensitive Naϩ-ClϪ cotransporter (NCC), which plays a key role in modulating salt and fluid delivery to downstream portions of the nephron and, in Kϩ secretion
Two inherited diseases, which are the consequence of the elimination or activation of NCC, produce opposite effects on plasma Kϩ concentration: Gitelman’s disease features hypokalemia, which is due to inactivating mutations in the gene encoding NCC (Slc12a3), and familial hyperkalemic hypertension or pseudohypoaldosteronism type II, a disease that features hyperkalemia, which may be the consequence of NCC activation by altered activity of mutant kinases or ubiquitin ligases, because it can be abrogated by either thiazide-type diuretics [19, 40] or the elimination of NCC in genetically engineered mice [17]
Summary
RENAL Kϩ EXCRETION is dependent on Kϩ secretion in the distal nephron because the filtered Kϩ is almost completely reabsorbed in the proximal convoluted tubule. Vallon et al [34] observed that mice fed a low-Kϩ diet exhibited a significant increase in activating phosphorylation of NCC, an effect that would be expected to decrease Naϩ and fluid delivery to the distal nephron, negatively affecting Kϩ secretion. Frindt and Palmer [10] observed a moderate decrease in NCC apical expression in rats maintained on a high-Kϩ diet. In this regard, it is important to note that a high-Kϩ diet is a strong stimulus for increasing the synthesis and secretion of the mineralocorticoid hormone aldosterone, which is known to promote increased NCC expression [16].
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