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 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 inositol-requiring 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.
Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
Béatrice
B
Bailly-Maitre
Constantino
C
Fondevila
Fady
F
Kaldas
Nathalie
N
Droin
Fréderic
F
Luciano
Jean-Ehrland
JE
Ricci
Rhonda
R
Croxton
Maryla
M
Krajewska
Juan M
JM
Zapata
Jerzy W
JW
Kupiec-Weglinski
Douglas
D
Farmer
John C
JC
Reed
D000818:Animals; D017209:Apoptosis; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D022781:Hepatocytes / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010100:Oxygen / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D015427:Reperfusion Injury / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D000637:Transaminases / Q000097:blood; D014157:Transcription Factors / Q000378:metabolism
D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; C490015:Tmbim6 protein, mouse; D014157:Transcription Factors; D000637:Transaminases; D005947:Glucose; D010100:Oxygen