Dietary salt modulates the sodium chloride cotransporter expression likely through an aldosterone-mediated WNK4-ERK1/2 signaling pathway

Abstract

WNK is a serine/threonine kinase. Mutation in WNK1 or WNK4 kinase results in pseudohypoaldosteronism type II (PHA II) featuring hypertension, hyperkalemia and metabolic acidosis. Sodium chloride cotransporter (NCC) is known to be regulated by phosphorylation and trafficking. Dietary salt and hormonal stimulation, such as aldosterone, also affect the regulation of NCC. We have previously reported that WNK4 inhibits NCC protein expression. To determine whether dietary salt affects NCC abundance through WNK4-mediated mechanism, we investigated the effects of dietary salt change with or without aldosterone infusion (1 mg/kg/day) on NCC and WNK4 expression in rats. We found that high-salt (HS, 4% NaCl) diet significantly inhibits NCC mRNA expression and protein abundance while enhancing WNK4 mRNA and protein expression, whereas low-salt (LS, 0.07% NaCl) diet increases NCC mRNA expression and protein abundance while reducing WNK4 expression. We also found that aldosterone infusion in HS-fed rats increases NCC mRNA expression and protein abundance, but decreases WNK4 expression. Administration with spironolactone (0.1 g/kg/day) in LS-fed rats decreases NCC mRNA expression and protein abundance while increasing WNK4 expression. We further showed that ERK1/2 phosphorylation was increased in HS-fed rats, but decreased in LS-fed rats. In HEK293 cells, over-expressed WNK4 increases ERK1/2 phosphorylation, whereas knockdown of WNK4 expression decreases ERK1/2 phosphorylation. Aldosterone treatment for 3 h decreases ERK1/2 phosphorylation. These data suggest that dietary salt change affects NCC protein abundance in an aldosterone-dependent mechanism likely via the WNK4-ERK1/2-mediated pathway.

Mechanism of Salt-Sensitive Hypertension

“…64,65 Aldosterone also participates in the dietary salt-induced modulation of NCC protein levels through the WNK4-extracellular signalregulated kinase 1/2 signaling pathway. 63 We revealed the involvement of the renal SNS in salt-induced changes in WNK4 expression and NCC activity in salt-sensitive hypertensive rats. 17 Salt loading in DOCAtreated rats resulted in increased SNS activity and decreased WNK4 expression in the kidneys.…”

“…65 Aldosterone also activates NCC through either the WNK4-SPAKdependent 70 or the WNK4-extracellular signal-regulated kinase 1/2 signaling pathway. 63 Therefore, we can speculate on the involvement of AII or aldosterone in NCC activation by b-AR stimulation; however, neither an MR antagonist nor an angiotensin receptor blocker affected salt-induced elevation of BP in isoproterenol-infused mice or the isoproterenol-induced downregulation of WNK4 levels. It remains unknown whether b-AR stimulation activates SPAK/oxidative stress responsive kinase-1 independently of AII and aldosterone.…”

“…61 Several investigators report that the expression of WNK kinases is modulated by changes in dietary sodium and therefore, influences NCC activity. 17,62,63 The low-salt diet in Sprague Dawley rats decreases the renal expression of WNK4 and increases NCC activity in the kidney. 63 Changes in dietary salt intake influence neurohumoral factors, such as the circulating RAS and SNS, and, thus, modulate the WNK4-NCC pathway.…”

“…17,62,63 The low-salt diet in Sprague Dawley rats decreases the renal expression of WNK4 and increases NCC activity in the kidney. 63 Changes in dietary salt intake influence neurohumoral factors, such as the circulating RAS and SNS, and, thus, modulate the WNK4-NCC pathway. AII is involved in NCC activation on a low-salt diet in an STE20/SPS-1-related proline/alanine-rich kinase (SPAK)-dependent manner.…”

Activation of the renal Na + :Cl − cotransporter by angiotensin II is a WNK4-dependent process

“…A recent work shows that variations in salt diet in rats induce opposite effects in NCC and WNK4 mRNA levels (29). Interestingly, contradictory observations also exist in adult mice in which WNK4 expression is changed by pharmacologic interventions.…”