Protective Effect of Carbon Monoxide-Releasing Molecules in Renal Ischemia-Reperfusion Injury Is Associated with Profound Inhibition of HMGB1 Cytoplasmic Translocation, The
Institue of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
Meeting: 2013 American Transplant Congress
Abstract number: D1550
Background: carbon monoxide-releasing molecules (CORMs) can significantly protect against renal ischemia-reperfusion injury (IRI), however, the mechanisms have not been fully elucidated. HMGB1 can be passively released by ischemic cells and serve as an essential early mediator of injury and inflammation in IRI. In this study, we investigated whether the protective effect of CORMs in renal IRI is associated with the inhibition of ischemia-induced HMGB1 releasing.
Methods: Renal IRI was induced by clamping the left renal pedicle for 50 min in uninephrectomized BALB/c mice. A single dose of CORM-2 (20 mg/kg) was given intravenously 1 hr before the renal ischemia. Mice treated with PBS or inactivated CORM-2 (iCORM-2) were used as controls. IRI was evaluated using kidney histopathology, immunopathology, BUN, serum creatinine, and survival. Cytoplasmic HMGB1 in kidney tissues was determined by Western blot. Additionally, isolated primary mouse renal proximal tubular epithelial cells (MRPTEpiC) with or without CORM-2 pre-treatment were cultured in hypoxic medium for various time points. Cytoplasmic HMGB1 was determined by Western blot and confocal immunofluorescence imaging. Acetylated HMGB1 was measured by co-immunoprecipitation.
Results: Following 50 min of ischemia, all control mice died within 3 days due to acute renal failure, whereas CORM-2 pretreatment significantly protected against this lethal IRI, all mice in this group survived long-term with almost normal renal function and histology. Additionally, administration of CORM-2 was associated with marked reduction in tubular apoptosis and inflammation (TNF-Α, IL-6 and IL-1Β expression) in situ. Ischemia alone significantly induced HMGB1 cytoplasmic translocation in the kidneys of control mice, whereas CORM-2 treatment almost completely inhibited the nucleocytoplasmic shuttling of HMGB1. This result was further confirmed in an in vitro ischemia-injury model using MRPTEpiC. Moreover, the inhibition of HMGB1 cytoplasmic translocation in MRPTEpiC by CORM-2 was found to be associated with the preservation of histone deacetylase (HDAC) activity in the nucleus.
Conclusion: Administration of CORM-2 profoundly protected against lethal renal IRI in mice. This potent protective effect was demonstrated to be associated with the inhibition of HMGB1 cytoplasmic translocation.
To cite this abstract in AMA style:
Chen G, Ruan Y, Wang L, Xiang Y, Guo H, Zhao Y. Protective Effect of Carbon Monoxide-Releasing Molecules in Renal Ischemia-Reperfusion Injury Is Associated with Profound Inhibition of HMGB1 Cytoplasmic Translocation, The [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/protective-effect-of-carbon-monoxide-releasing-molecules-in-renal-ischemia-reperfusion-injury-is-associated-with-profound-inhibition-of-hmgb1-cytoplasmic-translocation-the/. Accessed May 14, 2025.« Back to 2013 American Transplant Congress