Carbon monoxide potently prevents ischemia-induced high-mobility group box 1 translocation and release and protects against lethal renal ischemia–reperfusion injury

• DOI: 10.1038/ki.2014.80
• Publication Date: 2014-04-02T08:44:55Z
• Authors: Yongle Ruan; Lu Wang; Yue Zhao; Ying Yao; Song Chen; Junhua Li; Hui Guo; Changsheng Ming; Shi Chen; Feili Gong; Gang Chen
• Keywords: Cell Nucleus; Male; 0301 basic medicine; Carbon Monoxide; Mice, Inbred BALB C; Interleukin-6; Interleukin-1beta; Receptor for Advanced Glycation End Products; Active Transport, Cell Nucleus; Epithelial Cells; Mice; 03 medical and health sciences; Kidney Tubules; Organometallic Compounds; Animals; Cytokines; RNA, Messenger; HMGB1 Protein; Receptors, Immunologic; Cells, Cultured; Chemokine CCL2; Histone Acetyltransferases

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.