Premium
Hypoxia reverses dibutyryl‐cAMP‐induced stellation of cultured astrocytes via activation of the endothelin system
Author(s) -
Schmidt-Ott Kai M.,
Xu An Ding,
Tuschick Sebastian,
Liefeldt Lutz,
Kresse Wolfgang,
Verkhratsky Alexej,
Kettenmann Helmut,
Paul Martin
Publication year - 2001
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.00-0625fje
Subject(s) - hypoxia (environmental) , endothelin receptor , chemistry , microbiology and biotechnology , astrocyte , endocrinology , medicine , biology , biochemistry , central nervous system , receptor , oxygen , organic chemistry
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 dibutyryl‐cAMP. 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 down‐regulation of ET A receptor and ET B 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.