Carbon monoxide potently prevents ischemia-induced high-mobility group box 1 translocation and release and protects against lethal renal ischemia-reperfusion injury.
High-mobility group box 1 (HMGB1) is a chromatin-binding nuclear molecule that has potent proinflammatory effects once released by damaged cells. In some disease models, carbon monoxide (CO) exhibits anti-inflammatory and protective properties. Here, we investigated whether the protective effect of CO on renal ischemia-reperfusion injury is associated with the inhibition of HMGB1 translocation and release. A renal ischemia-reperfusion injury model was established with a 100% mortality rate in untreated mice. Pretreatment with the CO-releasing molecule-2 (CORM-2) resulted in 100% survival, maximal preservation of renal function, a marked reduction in pathological damage, and blunted upregulation of TLR4, RAGE, TNF-α, IL-1β, IL-6, and MCP1 mRNA. Interestingly, CORM-2 pretreatment almost completely inhibited ischemia-induced HMGB1 nucleocytoplasmic shuttling and release. This inhibition was associated with a decrease in nuclear histone acetyltransferase activity. Indeed, CORM-2 pretreatment inhibited the acetylation and release of HMGB1 during hypoxic culture of primary mouse renal tubular epithelia cells in vitro. Using the same renal ischemia-reperfusion injury model, neutralization of HMGB1 was protective, and administration of exogenous HMGB1 largely reversed the protective effect of CORM-2 on kidney ischemia-reperfusion injury. Thus, CORM-2-delivered CO protects against lethal renal ischemia-reperfusion injury. This protection is correlated with the prevention of HMGB1 nuclear-cytoplasmic translocation and release.
Institute of Organ Transplantation, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.
Yongle
Y
Ruan
Institute of Organ Transplantation, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.
Lu
L
Wang
Institute of Organ Transplantation, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.
Yue
Y
Zhao
Department of Nephrology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.
Ying
Y
Yao
Institute of Organ Transplantation, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.
Song
S
Chen
Department of Nephrology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.
Junhua
J
Li
Institute of Organ Transplantation, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.
Hui
H
Guo
1] Institute of Organ Transplantation, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China [2] Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China [3] Key Laboratory of Organ Transplantation, Ministry of Public Health, Wuhan, China.
Changsheng
C
Ming
1] Institute of Organ Transplantation, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China [2] Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China [3] Key Laboratory of Organ Transplantation, Ministry of Public Health, Wuhan, China.
Shi
S
Chen
Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Feili
F
Gong
1] Institute of Organ Transplantation, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China [2] Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China [3] Key Laboratory of Organ Transplantation, Ministry of Public Health, Wuhan, China.
Gang
G
Chen
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D002248:Carbon Monoxide / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics; D016207:Cytokines / Q000378:metabolism; D004847:Epithelial Cells; D024243:HMGB1 Protein / Q000378:metabolism*; D051548:Histone Acetyltransferases / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007684:Kidney Tubules; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009942:Organometallic Compounds / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control*; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014178:Translocation, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D016207:Cytokines; D024243:HMGB1 Protein; D053583:Interleukin-1beta; D015850:Interleukin-6; D009942:Organometallic Compounds; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C447082:tricarbonyldichlororuthenium (II) dimer; D002248:Carbon Monoxide; D051548:Histone Acetyltransferases