Cytoprotective Gene bi-1 Is Required for Intrinsic Protection from Endoplasmic Reticulum Stress and Ischemia-Reperfusion Injury

Ischemia-reperfusion (IR) injury induces endoplasmic reticulum (ER) stress and cell death. Bax Inhibitor-1 (BI-1) is an evolutionarily conserved ER protein that suppresses cell death and that is abundantly expressed in both liver and kidney. We explored the role of BI-1 in protection from ER stress...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2006-02, Vol.103 (8), p.2809-2814
Main Authors: Bailly-Maitre, Béatrice, Fondevila, Constantino, Kaldas, Fady, Droin, Nathalie, Luciano, Fréderic, Ricci, Jean-Ehrland, Croxton, Rhonda, Krajewska, Maryla, Zapata, Juan M., Kupiec-Weglinski, Jerzy W., Farmer, Douglas, Reed, John C.
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Biological Sciences
Cell death
Endoplasmic Reticulum - metabolism
Gene Expression
Genes
Glucose - metabolism
Heat-Shock Proteins - metabolism
Hepatocytes
Hepatocytes - chemistry
Hepatocytes - metabolism
Hepatocytes - pathology
Hypoxia
Injuries
Insulin resistance
Kidney - metabolism
Kidney - pathology
Kidneys
Liver
Liver - chemistry
Liver - metabolism
Liver - pathology
Membrane Proteins - deficiency
Membrane Proteins - genetics
Membrane Proteins - physiology
Mice
Mice, Knockout
Oxidative stress
Oxygen - metabolism
Physical trauma
Proteins
Reperfusion Injury - etiology
Reperfusion Injury - metabolism
Reperfusion Injury - pathology
RNA, Messenger - analysis
RNA, Messenger - metabolism
Rodents
Tissues
Transaminases - blood
Transcription Factors - metabolism
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Summary:Ischemia-reperfusion (IR) injury induces endoplasmic reticulum (ER) stress and cell death. Bax Inhibitor-1 (BI-1) is an evolutionarily conserved ER protein that suppresses cell death and that is abundantly expressed in both liver and kidney. We explored the role of BI-1 in protection from ER stress and IR injury by using bi-1 knockout mice, employing models of transient hepatic or renal artery occlusion. Compared to wild-type bi-1 mice, bi-1 knockout mice subjected to hepatic IR injury exhibited these characteristics: (i) increased histological injury; (ii) increased serum transaminases, indicative of more hepatocyte death; (iii) increased percentages of TUNEL-positive hepatocytes; (iv) greater elevations in caspase activity; and (v) more activation of ER stress proteins inositolrequiring enzyme 1 and activating transcription factor 6 and greater increases in expression of ER stress proteins C/EBP homologous protein and spliced XBP-1 protein. Moreover, hepatic IR injury induced elevations in bi-1 mRNA in wild-type liver, suggesting a need for bi-1 gene induction to limit tissue injury. Similar sensitization of kidney to ER stress and IR injury was observed in $bi-1^{-/-}$ mice. We conclude that bi-1 provides endogenous protection of liver and kidney from ER stress and IR injury. Analysis of components of the bi-1-dependent pathway for protection from IR injury may therefore reveal new strategies for organ preservation.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0506854103