title: Preconditioning with recombinant high-mobility group box 1 protein protects the kidney against ischemia-reperfusion injury in mice.
abstract: A preconditioning effect occurs when exposure to a nonharmful quantity of a mediator of injury provides protection against injury upon subsequent reexposure. High-mobility group box 1 (HMGB1) protein, an endogenous ligand for Toll-like receptor (TLR) 4, is a TLR4-dependent mediator of kidney ischemia-reperfusion injury. Here we determined whether preconditioning with recombinant HMGB1 can block kidney ischemia-reperfusion injury, whether this effect is TLR4 dependent and, if so, how preconditioning downregulates TLR signaling. Wild-type mice pretreated with rHMGB1 before ischemia were protected against kidney ischemia-reperfusion injury, indicated by lower serum creatinine, less tubular damage, less tubulointerstitial neutrophil and macrophage infiltration, and less tubular epithelial cell apoptosis versus control mice. Gene expression of TLR-downstream cytokines and chemokines in ischemia-reperfusion injury kidney were also significantly reduced. While TLR4 and TLR2 knockout mice were protected against kidney ischemia-reperfusion injury, HMGB1 preconditioning provided additional protection to TLR2 but not TLR4 knockout mice. The protective effect of rHMGB1 preconditioning involved Siglec-G upregulation, a negative regulator of HMGB1-mediated TLR4 pathway activation. Thus, preconditioning with rHMGB1 affords significant protection from TLR4-dependent kidney ischemia-reperfusion injury, indicating therapeutic potential.
authors.affiliation: 1] Renal Medicine, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia [2] Collaborative Transplant Research Group, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Huiling
authors.initials: H
authors.lastname: Wu
authors.affiliation: Collaborative Transplant Research Group, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Renske
authors.initials: R
authors.lastname: Steenstra
authors.affiliation: Collaborative Transplant Research Group, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Elianne C S
authors.initials: EC
authors.lastname: de Boer
authors.affiliation: Collaborative Transplant Research Group, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Cathy Y
authors.initials: CY
authors.lastname: Zhao
authors.affiliation: Collaborative Transplant Research Group, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Jin
authors.initials: J
authors.lastname: Ma
authors.affiliation: Collaborative Transplant Research Group, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Jorieke M
authors.initials: JM
authors.lastname: van der Stelt
authors.affiliation: 1] Renal Medicine, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia [2] Collaborative Transplant Research Group, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Chadban
mesh_terms: D058186:Acute Kidney Injury / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D018925:Chemokines / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D025461:Feedback, Physiological; D024243:HMGB1 Protein / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D019194:Ischemic Preconditioning / Q000379:methods*; D007668:Kidney / Q000187:drug effects; D037102:Lectins / Q000378:metabolism; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D011994:Recombinant Proteins / Q000627:therapeutic use; D015427:Reperfusion Injury / Q000517:prevention & control*; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D018925:Chemokines; D024243:HMGB1 Protein; D037102:Lectins; D016328:NF-kappa B; D011947:Receptors, Antigen, B-Cell; D011994:Recombinant Proteins; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; C522403:Siglecg protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4