DNA-Aptamer Raised against Receptor for Advanced Glycation End Products Improves Survival Rate in Septic Mice

Abstract

Despite remarkable scientific advances in the understanding of molecular mechanisms for sepsis, therapeutic options are far from satisfactory. High mobility group box 1 (HMGB1), one of the ligands of receptor for advanced glycation end products (RAGE), is a late mediator of lethality in septic mice. We have recently found that the DNA-aptamer raised against RAGE (RAGE-aptamer) significantly blocks experimental diabetic nephropathy and melanoma growth and metastasis. We examined the effects of RAGE-aptamer on sepsis score, survival rate, and inflammatory and oxidative stress responses in serum, peripheral monocytes, kidneys and livers of lipopolysaccharide- (LPS-) injected mice, and on LPS-exposed THP-1 cells. RAGE-aptamer inhibited the binding of HMGB1 to RAGE in vitro. RAGE-aptamer significantly (P=0.002) improved sepsis score at 8 hours after LPS injection and survival rate at 24 hours (P<0.01, 70%) in septic mice compared with LPS+vehicle- or LPS+control-aptamer-treated mice. RAGE-aptamer treatment significantly decreased expression of p-NF-κB p65, an active form of redox-sensitive transcriptional factor, NF-κB and gene or protein expression of TNF-α, IL-1β, IL-6, and HMGB1 in serum, peripheral monocytes, and kidneys of septic mice in association with the reduction of oxidative stress and improvement of metabolic acidosis, renal and liver damage. LPS-induced oxidative stress, inflammatory reactions, and growth suppression in THP-1 cells were significantly blocked by RAGE-aptamer. Our present study suggests that RAGE-aptamer could attenuate multiple organ damage in LPS-injected septic mice partly by inhibiting the inflammatory reactions via suppression of HMGB1-RAGE interaction.