Inhibitors of the proteasome stimulate the epithelial sodium channel (ENaC) through SGK1 and mimic the effect of aldosterone

Morag K. Mansley, Christoph Korbmacher*, Marko Bertog

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The epithelial sodium channel (ENaC) marks the tightly regulated, rate-limiting step of sodium re-absorption in the aldosterone-sensitive distal nephron (ASDN). Stimulation of ENaC activity by aldosterone involves the serum and glucocorticoid-induced kinase 1 (SGK1) and is mediated via complex mechanisms including inhibition of channel retrieval. Retrieved channels may be recycled or degraded, e.g. by the proteasomal pathway. The aim of the present study was to investigate whether inhibitors of the proteasome affect ENaC activity and surface expression, and to explore a possible involvement of SGK1. Short circuit current (ISC) measurements were performed on confluent mCCDcl1 murine cortical collecting duct cells to investigate the effect of two distinct proteasomal inhibitors, MG132 and bortezomib, on amiloride-sensitive ENaC-mediated ISC. Both inhibitors robustly stimulated amiloride-sensitive ISC. The time course and magnitude of the stimulatory effect of the proteasomal inhibitors on ISC were similar to those of aldosterone. Both, MG132 and aldosterone, significantly increased the abundance of β-ENaC at the cell surface. SGK1 activity was assessed by monitoring the phosphorylation of a downstream target, NDRG1, and was found to be increased by MG132. Importantly, inhibiting SGK1 activity prevented not only the stimulatory effect of aldosterone but also that of proteasomal inhibition. In conclusion, these data suggest that ENaC stimulation following proteasomal inhibition is due to an accumulation of active SGK1 resulting in increased expression of ENaC at the cell surface. Thus, inhibition of the proteasome mimics SGK1-dependent stimulation of ENaC by aldosterone.

Original languageEnglish
Pages (from-to)1-10
Number of pages10
JournalPflügers Archiv European Journal of Physiology
Early online date31 Aug 2017
DOIs
Publication statusE-pub ahead of print - 31 Aug 2017

Keywords

  • Aldosterone
  • ENaC
  • MG132
  • Proteasome
  • Renal collecting duct cells
  • SGK1

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