Association between soluble receptor for advanced glycation end products and a disintegrin and metalloproteinase 10 in Type 1 diabetes

Abstract

The receptor for advanced glycation end products (RAGE) plays an important role in the pathogenesis of diabetic complications and atherosclerosis. Soluble forms of the receptor (sRAGE) can act as decoy for RAGE ligands and counteract the detrimental action of the full-length receptor. Soluble RAGE is produced by alternative splicing [endogenous secretory RAGE (esRAGE)] and/or by proteolytic cleavage of the membrane-bound form of RAGE. It has been suggested that ectodomain shedding is one of the mechanisms for regulating the function of RAGE. A Disintegrin And Metalloproteinase (ADAM) is a major proteinase family that mediates ectodomain shedding of cell surface proteins. Our in vitro experiments showed that the RAGE shedding (both constitutive and insulin-induced) was significantly reduced after inhibition of the sheddase ADAM10 in macrophages. We further examined whether there was any relationship between ADAM10 and total sRAGE and esRAGE levels in type 1 diabetes. 102 type 1 diabetic patients and age- and sex-matched controls were recruited. Serum ADAM10 was measured by in-house competitive ELISA using a monoclonal anti-human ADAM10 antibody (Millipore, CA). Serum total sRAGE and esRAGE were assayed by commercial ELISA kits (Quantikine, R&D systems, MN, USA, and B-Bridge International Inc., CA, USA respectively). The difference between total sRAGE and esRAGE gave an estimated measure of soluble forms of RAGE formed by cleavage (cRAGE). Type 1 diabetic patients have higher serum total sRAGE [1038 (749-1217) pg/ml vs 802 (532-1129), median (interquartile range), p<0.01], esRAGE [367 (269-476) pg/ml vs 291 (214-389), p<0.01] and cRAGE [594 (447-812) pg/ml vs 484 (283-796), p<0.01] than controls. Serum ADAM10 was also increased in patients with type 1 diabetes [324 (179-433) ng/ml vs 156 (112-278), p<0.01]. Serum ADAM10 level correlated with serum cRAGE in type 1 diabetes (r=0.40, p<0.01) and in controls (r=0.31. p<0.01) but no correlations were seen with esRAGE. The association remained significant after adjusting for age, gender, body mass index and smoking status. In conclusion, our data suggested that ADAM10 contributed to the shedding of RAGE and ADAM10 level was significantly associated with serum cRAGE in type 1 diabetes and non-diabetic control.