PT  - JOURNAL ARTICLE
AU  - Yutaka Koyama
AU  - Ayano Ukita
AU  - Kana Abe
AU  - Kuniaki Iwamae
AU  - Shogo Tokuyama
AU  - Keisuke Tanaka
AU  - Yuki Kotake
TI  - Dexamethasone Down-regulates Endothelin Receptors and Reduces Endothelin-induced Production of Matrix Metalloproteinases in Cultured Rat Astrocytes
AID  - 10.1124/mol.116.107300
DP  - 2017 Jan 01
TA  - Molecular Pharmacology
PG  - mol.116.107300
4099  - http://molpharm.aspetjournals.org/content/early/2017/05/01/mol.116.107300.short
4100  - http://molpharm.aspetjournals.org/content/early/2017/05/01/mol.116.107300.full
AB  - 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 non-treated cells. Levels of ETA and ETB receptor proteins became about 50 % of non-treated 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 3 (MMP3) and MMP9 mRNAs, pre-treatment with Dex reduced ET-induced increases in MMP mRNAs. The effects of ET-1 on release of MMP3 and MMP9 proteins were attenuated by pre-treatment with Dex. ET-1 stimulated the phosphorylation of extracellular signal regulated kinase 1/2 (ERK1/2) in cultured astrocytes. Pre-treatment with Dex reduced the ET-induced increases in ERK1/2 phosphorylation. In contrast, pre-treatment 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 down-regulates astrocytic ET receptors and reduces ET-induced MMP production.