Receptor for advanced glycation end product (RAGE)-dependent modulation of early growth response-1 in hepatic ischemia/reperfusion injury.
OBJECTIVE
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.
Zeng
Shan
S
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
Dun
Hao
H
Ippagunta
Nikalesh
N
Rosario
Rosa
R
Zhang
Qing Y
QY
Lefkowitch
Jay
J
Yan
Shi F
SF
Schmidt
Ann Marie
AM
Emond
Jean C
JC
D000818:Animals; D017209:Apoptosis; D054426:Chemokine CXCL2 / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism / Q000473:pathology; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases