EGCG-rich green tea extract stimulates sRAGE secretion to inhibit S100A12-RAGE axis through ADAM10-mediated ectodomain shedding of extracellular RAGE in type 2 diabetes

The receptor for advanced glycation of end products (RAGE) plays a critical role in the progression of type 2 diabetes (T2D). Soluble RAGE (sRAGE) is one of the RAGE variants, which acts as a decoy domain receptor and competes with RAGE, thus contributing to prevention of T2D. In this study, we conducted clinical trials of (-)-epigallocatechin-3-gallate (EGCG) rich green tea extract (300-900 mg/day) to investigate the effect of EGCG on relationship between S100A12 RAGE ligand and diverse sRAGE in T2D. Moreover, mechanism of sRAGE production also confirmed in vitro. Our data indicated that EGCG could stimulate sRAGE circulation but inhibited RAGE ligand in T2D, and ADAM10-mediated ectodomain shedding of extracellular RAGE was mainly involved in EGCG-stimulated sRAGE circulation. The present evidence indicates that EGCG has a potential to block S100A12-RAGE axis by stimulating sRAGE production through ADAM10-mediated ectodomain shedding of extracellular RAGE. Therefore, EGCG contributes to nutritional strategies for diabetes, not only because of its efficient antioxidant activity to scavenge free radicals, but also because of its ability stimulating sRAGE release in the circulation. Additionally, ADAM10-induced ectodomain shedding of extracellular RAGE leading to sRAGE circulation should be a potential of passive mechanism of sRAGE production to block S100A12-RAGE axis-related pathogenesis of proinflammation and diabetes.