Plastic Surgery Research Council
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SILENCE THE RAGE: TARGETED INHIBITION OF THE RECEPTOR FOR ADVANCED GLYCATED ENDPRODUCTS (RAGE) RESTORES REGENERATIVE FUNCTION IN DIABETES
Presenter: Stelios C Wilson, BA
Co-Authors: Lalezarzadeh F; Soares MA; Lotfi P; Ham MJ; OJO CO; Sartor RA; Saadeh PB; Ceradini DJ
Predoctoral Research Fellow

Introduction: RAGE, a cell surface receptor for advanced glycation endproducts (AGEs), pathologically accumulates in diabetic tissue. Increased signaling through the RAGE/AGE axis activates several adverse metabolic cellular pathways including overproduction of ROS, which results in cellular dysfunction. Here we examined the impact of targeted RAGE inhibition in the regenerative niche on cutaneous wound healing.

Methods: Stented wounds were created on the dorsum of diabetic (DB), wild-type (WT), and RAGE KO (RAGE-/-) mice and were treated with RAGE or nonsense siRNA. RAGE and associated gene mRNA expression and protein concentration were quantified by real time RTPCR and western blot. Endproducts of ROS overproduction were determined using 8-OHdG ELISA. Time to wound closure was measured photometrically and histologically.

Results: RAGE expression in DB wounds was 3-fold higher than WT (p<0.01). RAGE silencing resulted in an 82% reduction in RAGE expression (p<0.001), altering expression of several downstream oxidant enzymes (NOX4 53% reduction, p<0.05; MnSOD 65% reduction, p<0.01). Further, RAGE silencing resulted in 79% reduction in levels of 8-OHdG (p<0.001). In DB wounds, RAGE silencing improved epithelial gap area at day 8 (56.6% vs 70.2%; p<0.05), and day 15 (32.0% vs 51.6%; p<0.05), and ultimately accelerated time to wound closure (22 vs 29 days; p<0.01). Despite this clinical effect, RAGE silencing had no effect on WT wound closure (12 vs 12 days; p>0.05) nor was there a difference between RAGE-/- and WT wound closure (12 vs 12 days; p>0.05).

Conclusion: Here we demonstrate that the diabetic regenerative environment is compromised by increased RAGE expression and signaling. Targeting RAGE with topical therapeutic siRNA reverses this dysfunction and significantly improves tissue regeneration despite ongoing hyperglycemia. Topical RAGE silencing is a novel therapeutic strategy that can be rapidly translated to clinical use.


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