Serum Level of Soluble Receptor for Advanced Glycation End Products Is Associated with A Disintegrin And Metalloproteinase 10 in Type 1 Diabetes.
BACKGROUND
The receptor for advanced glycation end products (RAGE) is involved in the pathogenesis of diabetic complications, and soluble forms of the receptor (sRAGE) can counteract the detrimental action of the full-length receptor by acting as decoy. Soluble RAGE is produced by alternative splicing [endogenous secretory RAGE (esRAGE)] and/or by proteolytic cleavage of the membrane-bound receptor. We have investigated the role of A Disintegrin And Metalloproteinase 10 (ADAM10) in the ectodomain shedding of RAGE.


METHODS
Constitutive and insulin-induced shedding of RAGE in THP-1 macrophages by ADAM10 was evaluated using an ADAM10-specific metalloproteinase inhibitor. Serum ADAM10 level was measured in type 1 diabetes and control subjects, and the association with serum soluble RAGE was determined. Serum total sRAGE and esRAGE were assayed by ELISA and the difference between total sRAGE and esRAGE gave an estimated measure of soluble RAGE formed by cleavage (cRAGE).


RESULTS
RAGE shedding (constitutive and insulin-induced) was significantly reduced after inhibition of ADAM10 in macrophages, and insulin stimulated ADAM10 expression and activity. Diabetic subjects have higher serum total sRAGE and esRAGE (p<0.01) than controls, and serum ADAM10 was also increased (p<0.01). Serum ADAM10 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, BMI, smoking status and HbA1c.


CONCLUSIONS
Our data suggested that ADAM10 contributed to the shedding of RAGE. Serum ADAM10 level was increased in type 1 diabetes and was a significant determinant of circulating cRAGE.
Department of Medicine, University of Hong Kong, Hong Kong, China.
Alan C H
AC
Lee
Department of Medicine, University of Hong Kong, Hong Kong, China.
Joanne K Y
JK
Lam
Department of Medicine, University of Hong Kong, Hong Kong, China.
Sammy W M
SW
Shiu
Department of Medicine, University of Hong Kong, Hong Kong, China.
Ying
Y
Wong
Department of Medicine, Royal Free & University College London Medical School, London, United Kingdom.
D John
DJ
Betteridge
Department of Medicine, University of Hong Kong, Hong Kong, China.
Kathryn C B
KC
Tan
D051722:ADAM Proteins / Q000097:blood*; D000072197:ADAM10 Protein; D000328:Adult; D053829:Amyloid Precursor Protein Secretases / Q000097:blood*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood*; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000097:blood*; D008875:Middle Aged; D000067759:Receptor for Advanced Glycation End Products / Q000097:blood*
D051722:ADAM Proteins; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases; D008565:Membrane Proteins; D000067759:Receptor for Advanced Glycation End Products; C491236:ADAM10 protein, human; C000593871:AGER protein, human