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, TNF alpha, 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