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A more recent version of this article appeared on December 15, 2000
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M006512200v1
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Papers In Press, published online ahead of print September 8, 2000
J. Biol. Chem, 10.1074/jbc.M006512200
Submitted on July 21, 2000
Accepted on September 8, 2000

Coordinated up-regulation by hypoxia of adrenomedullin and one of its putative receptor (RDC-1) in cells of the rat blood brain barrier

Annie Ladoux and Christian Frelin

Institut de Pharmacologie Moleculaire et Cellulaire, CNRS UPR 411, Sophia Antipolis, Valbonne 06560

Corresponding Author: ladoux{at}ipmc.cnrs.fr

Adrenomedullin (ADM) is a potent hypotensive peptide, which is produced during sepsis and ischemia. We demonstrate here that hypoxia induced a time-dependent increase of both ADM mRNA and protein expressions in cultured astrocytes and endothelial cells from rat brain microvessels (RBEC). Gene reporter analyses showed a 2-fold increase in ADM gene transcription which was suppressed when the ADM promoter was deleted of its hypoxia responsive element. Hypoxia increased 7-fold the stability of preformed ADM mRNAs. RBECs expressed mRNAs coding for the different putative ADM receptors but they did not respond to exogenous ADM and CGRP by the formation of cAMP. In contrasts, ADM and CGRP increased the formation of cAMP in astrocytes and their actions were potentiated about 2-fold after hypoxia. Messenger RNA species coding for three putative ADM receptors (the L1 orphan receptor, RDC-1 and CRLR) and accessory proteins (RAMPs) were present in astrocytes. Hypoxia selectively upregulated expression of RDC-1 receptor mRNAs. The results indicate that ADM and RDC-1 are hypoxia sensitive genes and that RDC-1 receptors may mediate some actions of ADM in hypoxic astrocytes.


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