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Hypoxia reverses dibutyryl-cAMP-induced stellation of cultured astrocytes via activation of the endothelin system

Item Type:Article
Title:Hypoxia reverses dibutyryl-cAMP-induced stellation of cultured astrocytes via activation of the endothelin system
Creators Name:Schmidt-Ott, K.M. and Xu, A.D. and Tuschick, S. and Liefeldt, L. and Kresse, W. and Verkhratsky, A. and Kettenmann, H. and Paul, M.
Abstract:Hypoxic damage to the central nervous system triggers morphological and functional responses in astrocytes (AC). When isolated from the cerebral microenvironment and placed in cell culture, hypoxia promotes astrocytic alterations indicative of dedifferentiation. To investigate the effect of hypoxia on AC morphology, we performed studies on cultured AC pretreated with dibutyrylcAMP. These treated cells resemble AC in vivo, assuming a stellate morphology as observed by phase contrast microscopy. Exposure to hypoxia (0.3% oxygen tension) for 24 h induced a flat and polygonal shape in most of the cells as opposed to normoxic controls. A candidate factor to mediate this response is endothelin-1 (ET-1), a peptide produced by ischemic AC in vivo. The role of the astrocytic ET system during hypoxia, therefore, was investigated. Exogenous application of ET-1 mimicked the effect of hypoxia on the astrocytic morphology. The effects of hypoxia and exogenous ET-1 on the morphology were inhibited by the nonselective ET receptor antagonists PD142893 and PD145065. The ET peptide levels in the culture supernatants of AC increased about 1.5-fold after 24 h of hypoxia as measured by radioimmunoassay. Northern blot analyses revealed a threefold up-regulation of prepro ET-1 mRNA and a concomitant downregulation of ETA receptor and ETB receptor mRNAs. However, calcium responses were still inducible by exogenous ET-1. These results indicate that hypoxia triggers an autocrine loop in AC, resulting in a morphological transformation. This response is independent from neuronal damage and is based on activation of the astrocytic ET system.
Keywords:Cell Morphology, Astrocytes, Cultured Cells, Culture Media, Endothelin-1, Endothelin Converting Enzyme
Source:FASEB Journal
Publisher:Federation of American Societies for Experimental Biology
Page Range:1227-1229
Date:May 2001
Official Publication:https://doi.org/10.1096/fj.00-0625fje
PubMed:View item in PubMed

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