Abstract

Aldosterone binds to the mineralocorticoid receptor (MR) and increases renal Na(+) reabsorption via up-regulation of the epithelial Na(+) channel (ENaC) and the Na(+)-K(+)-ATPase in the collecting system (CS) and possibly also via the NaCl cotransporter (NCC) in the distal convoluted tubule (DCT). However, whether aldosterone directly regulates NCC via MR or indirectly through systemic alterations remains controversial. We used mice with deletion of MR in ∼20% of renal tubule cells (MR/X mice), in which MR-positive (MR(wt)) and -negative (MR(ko)) cells can be studied side-by-side in the same physiological context. Adult MR/X mice showed similar mRNA and protein levels of renal ion transport proteins to control mice. In MR/X mice, no differences in NCC abundance and phosphorylation was seen between MR(wt) and MR(ko) cells and dietary Na(+) restriction up-regulated NCC to similar extent in both groups of cells. In contrast, MR(ko) cells in the CS did not show any detectable alpha-ENaC abundance or apical targeting of ENaC neither on control diet nor in response to dietary Na(+) restriction. Furthermore, Na(+)-K(+)-ATPase expression was unaffected in MR(ko) cells of the DCT, while it was lost in MR(ko) cells of the CS. In conclusion, MR is crucial for ENaC and Na(+)-K(+)-ATPase regulation in the CS, but is dispensable for NCC and Na(+)-K(+)-ATPase regulation in the DCT.

Highlights

  • Aldosterone is important for the control of sodium (Na+) homeostasis and extracellular volume and blood pressure

  • The aldosterone - mineralocorticoid receptor (MR) signaling axis is critical for ion- and extracellular volume homeostasis, as highlighted in our study by the 100% perinatal lethality of the MRlox/lox and heterozygous for cmv-cre expression (MR/X) mice

  • We were able to detect a stimulation of NaCl cotransporter (NCC) by dietary Na+ restriction, we did not find any evidence for a regulatory role of the MR for NCC abundance and phosphorylation

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Summary

Introduction

Aldosterone (aldo) is important for the control of sodium (Na+) homeostasis and extracellular volume and blood pressure It stimulates Na+ reabsorption in aldo-sensitive epithelia in the kidney, colon, and sweat glands and elicits its effects by binding to the mineralocorticoid receptor (MR). It is important to note that the enzyme 11-β-hydroxysteroid-dehydrogenase type 2 (11βHSD2), protecting the MR from activation by glucocorticoids through rapid metabolization of cortisol in humans and corticosterone in rodents, is significantly expressed only in the endportion of the DCT (DCT2) and the CS [2, 5, 10]. This expression pattern of 11βHSD2 raises the important question of how aldosterone can activate the MR in the DCT in the presence of 100-1000 times higher glucocorticoid plasma levels

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