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

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 mCCD_cl1 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.

SUBMITTER: Mansley MK 

PROVIDER: S-EPMC6965672 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature