Dietary sodium alters aldosterone's effect on renal sodium transporter expression and distal convoluted tubule remodelling

Abstract

Aldosterone is responsible for maintaining volume and potassium homeostasis. Although high salt consumption should suppress aldosterone production, individuals with hyperaldosteronism lose this regulation, leading to a state of high aldosterone despite dietary sodium consumption. The present study examines the effects of elevated aldosterone, with or without high salt consumption, on the expression of key Na+ transporters and remodelling in the distal nephron. Epithelial sodium channel (ENaC) α‐subunit expression was increased with aldosterone regardless of Na+ intake. However, ENaC β‐ and γ‐subunits unexpectedly increased at both a transcript and protein level with aldosterone when high salt was present. Expression of total and phosphorylated Na+Cl− cotransporter (NCC) significantly increased with aldosterone, in association with decreased blood [K+], but the addition of high salt markedly attenuated the aldosterone‐dependent NCC increase, despite equally severe hypokalaemia. We hypothesized this was a result of differences in distal convoluted tubule length when salt was given with aldosterone. Imaging and measurement of the entire pNCC‐positive tubule revealed that aldosterone alone caused a shortening of this segment, although the tubule had a larger cross‐sectional diameter. This was not true when salt was given with aldosterone because the combination was associated with a lengthening of the tubule in addition to increased diameter, suggesting that differences in the pNCC‐positive area are not responsible for differences in NCC expression. Together, our results suggest the actions of aldosterone, and the subsequent changes related to hypokalaemia, are altered in the presence of high dietary Na+. imageKey points Aldosterone regulates volume and potassium homeostasis through effects on transporters in the kidney; its production can be dysregulated, preventing its suppression by high dietary sodium intake. Here, we examined how chronic high sodium consumption affects aldosterone's regulation of sodium transporters in the distal nephron. Our results suggest that high sodium consumption with aldosterone is associated with increased expression of all three epithelial sodium channel subunits, rather than just the alpha subunit. Aldosterone and its associated decrease in blood [K+] lead to an increased expression of Na‐Cl cotransporter (NCC); the addition of high sodium consumption with aldosterone partially attenuates this NCC expression, despite similarly low blood [K+]. Upstream kinase regulators and tubule remodelling do not explain these results.

Myeloid Cell Glucocorticoid, Not Mineralocorticoid Receptor Signaling, Contributes to Salt-Sensitive Hypertension in Humans via Cortisol

“…In previous studies, we showed that chronic treatment of salt and aldosterone induces blood pressure elevations secondary to renal tubular remodeling. 40 However, we found that plasma aldosterone levels do not correlate with SSBP in humans. 35 In the current studies, we demonstrate that changes in both plasma and urine cortisol correlate with human SSBP ( Figure 2 ).…”

“…39 We demonstrated previously the essential role of APC SGK1 in SSBP. 8,15 Whereas the role of SGK1 activation downstream of MR activation by aldosterone has been extensively studied in chronic salt-induced hypertension secondary to renal perturbations, 40 the mechanism of SGK1 activation in the context of acute blood pressure changes according to salt-intake (SSBP) has not been studied. Here we show that myeloid APCs lack MR expression but instead, we demonstrate high levels of GR expression in these cells (Figure 1).…”