Preconditioning with recombinant high-mobility group box 1 protein protects the kidney against ischemia-reperfusion injury in mice

• Published in: Kidney international Vol. 85; no. 4; p. 824
• Main Authors: Wu, Huiling, Steenstra, Renske, de Boer, Elianne C S, Zhao, Cathy Y, Ma, Jin, van der Stelt, Jorieke M, Chadban, Steven J
• Format: Journal Article
• Language: English
• Published: United States 01-04-2014
• Subjects: Acute Kidney Injury - prevention & control; Animals; Apoptosis - drug effects; Chemokines - drug effects; Drug Evaluation, Preclinical; Feedback, Physiological; HMGB1 Protein - metabolism; HMGB1 Protein - pharmacology; HMGB1 Protein - therapeutic use; Ischemic Preconditioning - methods; Kidney - drug effects; Lectins - metabolism; Male; Mice, Inbred BALB C; Mice, Inbred C57BL; NF-kappa B - metabolism; Receptors, Antigen, B-Cell - metabolism; Recombinant Proteins - therapeutic use; Reperfusion Injury - prevention & control; Toll-Like Receptor 4 - metabolism
• ISSN: 1523-1755
• DOI: 10.1038/ki.2013.475

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.