Abstract
In brain disorders, astrocytes change phenotype to reactive astrocytes and are involved in the induction of neuroinflammation and brain edema. The administration of glucocorticoids (GCs), such as dexamethasone (Dex), reduces astrocytic activation, but the mechanisms underlying this inhibitory action are not well understood. Endothelins (ETs) promote astrocytic activation. Therefore, the effects of Dex on ET receptor expressions were examined in cultured rat astrocytes. Treatment with 300 nM Dex for 6–48 hours reduced the mRNA expression of astrocytic ETA and ETB receptors to 30–40% of nontreated cells. Levels of ETA and ETB receptor proteins became about 50% of nontreated cells after Dex treatment. Astrocytic ETA and ETB receptor mRNAs were decreased by 300 nM hydrocortisone. The effects of Dex and hydrocortisone on astrocytic ET receptors were abolished in the presence of mifepristone, a GC receptor antagonist. Although Dex did not decrease the basal levels of matrix metalloproteinase (MMP) 3 and MMP9 mRNAs, pretreatment with Dex reduced ET-induced increases in MMP mRNAs. The effects of ET-1 on the release of MMP3 and MMP9 proteins were attenuated by pretreatment with Dex. ET-1 stimulated the phosphorylation of extracellular signal–regulated kinase 1/2 (ERK1/2) in cultured astrocytes. Pretreatment with Dex reduced the ET-induced increases in ERK1/2 phosphorylation. In contrast, pretreatment with Dex did not affect MMP production or ERK1/2 phosphorylation induced by phorbol myristate acetate, a protein kinase C activator. These results indicate that Dex downregulates astrocytic ET receptors and reduces ET-induced MMP production.
Footnotes
- Received October 27, 2016.
- Accepted April 25, 2017.
This work was supported by a Grant-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science [Grant 15K07981].
No potential conflicts of interest relevant to this article are reported.
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- Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics
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