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J Hepatol. 2009 May;50(5):929-36. doi: 10.1016/j.jhep.2008.11.022. Epub 2009 Jan 14.

Receptor for advanced glycation end product (RAGE)-dependent modulation of early growth response-1 in hepatic ischemia/reperfusion injury.

Author information

1
Division of Liver Diseases and Transplantation, Department of Surgery, College of Physicians & Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, USA. sz98@columbia.edu

Abstract

BACKGROUND/AIMS:

We previously showed that blockade of RAGE significantly attenuates hepatic ischemia/reperfusion (I/R) injury in mice. Here, we identify that early growth response-1 (Egr-1) is a downstream target of RAGE in hepatic I/R injury.

METHODS:

Hepatic I/R was induced in male mice. Liver remnants were analyzed for induction of Egr-1 and cytokines, as well as regulation of apoptotic pathways after reperfusion.

RESULTS:

Egr-1 was upregulated in the liver remnants after hepatic I/R injury and was suppressed by administration of soluble RAGE or deletion of the RAGE gene. RAGE-mediated increased expression of Egr-1 upregulates a central downstream gene, MIP2. In contrast, RAGE-stimulated Egr-1-independent pathways regulate TNF-alpha production and apoptosis in response to I/R. Consistent with these findings, phospho-p44/42 and phospho-JNK MAPK and c-Jun were strikingly suppressed in RAGE(-/-) versus WT mice, but not in Egr-1(-/-) mice. RAGE ligand HMGB1 was upregulated after I/R in the liver remnants. In vitro, incubation of RAGE-expressing liver dendritic cells (DCs) with recombinant HMGB-1 resulted in increased Egr-1 transcripts, in a manner suppressed by RAGE gene deletion, soluble RAGE and inhibitors of p44/p42 or JNK MAP kinase.

CONCLUSIONS:

Suppression of Egr-1 may contribute to the protective mechanisms underlying the beneficial impact of RAGE blockade or deletion.

PMID:
19303658
DOI:
10.1016/j.jhep.2008.11.022
[Indexed for MEDLINE]
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