Dexamethasone Downregulates Endothelin Receptors and Reduces Endothelin-Induced Production of Matrix Metalloproteinases in Cultured Rat Astrocytes
| Autor: | Kuniaki Iwamae, Yuki Kotake, Shogo Tokuyama, Keisuke Tanaka, Yutaka Koyama, Ayano Ukita, Kana Abe |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
medicine.hormone endocrine system medicine.medical_specialty MMP3 medicine.drug_class Anti-Inflammatory Agents Down-Regulation Biology Dexamethasone Endothelins 03 medical and health sciences 0302 clinical medicine Internal medicine polycyclic compounds medicine Animals Rats Wistar Receptor Neuroinflammation Cells Cultured Pharmacology Dose-Response Relationship Drug Kinase Receptors Endothelin Receptor antagonist Rats 030104 developmental biology Endocrinology Matrix Metalloproteinase 9 Astrocytes Molecular Medicine Phosphorylation Matrix Metalloproteinase 3 Endothelin receptor hormones hormone substitutes and hormone antagonists 030217 neurology & neurosurgery |
| Zdroj: | Molecular pharmacology. 92(1) |
| ISSN: | 1521-0111 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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