Trichostatin A blocks aldosterone-induced Na+ transport and control of serum- and glucocorticoid-inducible kinase 1 in cortical collecting duct cells

Morag K. Mansley*, Andrew J. Roe, Sarah L. Francis, Jason H. Gill, Matthew A. Bailey, Stuart M. Wilson

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

Abstract

Background and Purpose: Aldosterone stimulates epithelial Na+ channel (ENaC)-dependent Na+ retention in the cortical collecting duct (CCD) of the kidney by
activating mineralocorticoid receptors that promote expression of serum and glucocorticoid-inducible kinase 1 (SGK1). This response is critical to BP homeostasis. It has previously been suggested that inhibiting lysine deacetylases (KDACs) can post-transcriptionally disrupt this response by promoting acetylation of the mineralocorticoid receptor. The present study critically evaluates this hypothesis.

Experimental Approach: Electrometric and molecular methods were used to define the effects of a pan-KDAC inhibitor, trichostatin A, on the responses to a
physiologically relevant concentration of aldosterone (3 nM) in murine mCCDcl1 cells.

Key Results: Aldosterone augmented ENaC-induced Na+ absorption and increased SGK1 activity and abundance, as expected. In the presence of trichostatin A, these responses were suppressed. Trichostatin A-induced inhibition of KDAC was confirmed by increased acetylation of histone H3, H4, and α-tubulin. Trichostatin A did not block the electrometric response to insulin, a hormone that activates SGK1 independently of increased transcription, indicating that trichostatin A has no direct effect upon the SGK1/ENaC pathway.
Conclusions and Implications: Inhibition of lysine de-acetylation suppresses aldosterone-dependent control over the SGK1–ENaC pathway but does not perturb post-transcriptional signalling, providing a physiological basis for the anti-hypertensive action of KDAC inhibition seen in vivo.
Original languageEnglish
Pages (from-to)4708-4719
Number of pages12
JournalBritish Journal of Pharmacology
Volume176
Issue number24
Early online date25 Oct 2019
DOIs
Publication statusPublished - 16 Jan 2020

Fingerprint

Dive into the research topics of 'Trichostatin A blocks aldosterone-induced Na+ transport and control of serum- and glucocorticoid-inducible kinase 1 in cortical collecting duct cells'. Together they form a unique fingerprint.

Cite this