HMGB1 contributes to kidney ischemia reperfusion injury.
High-mobility group box 1 (HMGB1), a nuclear factor released extracellularly as an inflammatory cytokine, is an endogenous ligand for Toll-like receptor 4 (TLR4). TLR4 activation mediates kidney ischemia-reperfusion injury (IRI), but whether HMGB1 contributes to IRI is unknown. Here, treating wild-type mice with neutralizing anti-HMGB1 antibody protected them against kidney IRI, evidenced by lower serum creatinine and less tubular damage than untreated mice. Mice treated with anti-HMGB1 had significantly less tubulointerstitial infiltration by neutrophils (day 1) and macrophages (day 5) and markedly reduced apoptosis of tubular epithelial cells. Furthermore, anti-HMGB1 antibody-treated IRI kidneys had significantly lower levels of IL-6, TNFα, and monocyte chemoattractant protein 1 (MCP1). mRNA, which are downstream of HMGB1. Conversely, administration of rHMGB1 after reperfusion exacerbated kidney IRI in wild-type mice. TLR4 deficient (TLR4(-/-)) mice were protected against kidney IRI; administration of neither anti-HMGB1 antibody nor rHMGB1 affected this renoprotection. In conclusion, endogenous HMGB1 promotes kidney damage after IRI, possibly through the TLR4 pathway. Administration of a neutralizing antibody to HMGB1 either before or soon after ischemia-reperfusion affords significant protection, suggesting therapeutic potential for acute kidney injury.
Wu
Huiling
H
Collaborative Transplant Research Group, Royal Prince Alfred Hospital, Sydney, Australia. huiling.wu@sydney.edu.au
Ma
Jin
J
Wang
Peng
P
Corpuz
Theresa M
TM
Panchapakesan
Usha
U
Wyburn
Kate R
KR
Chadban
Steven J
SJ
D058186:Acute Kidney Injury / Q000378:metabolism* / Q000517:prevention & control; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D018932:Chemokine CCL2 / Q000378:metabolism; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D024243:HMGB1 Protein / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D015427:Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000888:Antibodies, Anti-Idiotypic; D018932:Chemokine CCL2; D024243:HMGB1 Protein; D015850:Interleukin-6; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha