In this study, AGEs stimulated the release of DPP-4 from HUVECs, which was significantly inhibited by the treatment with an anti-oxidant, NAC, RAGE-Ab, or linagliptin. Moreover, H
2O
2 dose-dependently increased the production of soluble DPP-4 by HUVECs. So, the AGE-RAGE-induced ROS generation could be involved in soluble DPP-4 generation by HUVECs. The present findings have extended our previous observations [
17] showing that serum levels of AGEs were independently correlated with circulating DPP-4 values in 432 consecutive outpatients and that AGEs significantly increase soluble DPP-4 release from cultured proximal tubular cells, one of the major cell types that expressed DPP-4 in humans [
26]. Since we previously reported that AGEs at 100 μg/ml for 4 hr did not affect DPP-4 mRNA levels in HUVECs [
27], the AGE-RAGE interaction might promote the proteolytic cleavage of membrane-bound DPP-4 from HUVECs via superoxide generation. Serum levels of AGEs are positively
rather than inversely associated with soluble form of RAGE (sRAGE) (endogenous secretory RAGE plus cleaved RAGE) in both diabetic and non-diabetic subjects [
28,
29]. Therefore, although exogenously administered sRAGE was shown to block the harmful effects of AGEs in animals by acting as a decoy receptor, it is questionable that sRAGE in humans could also exert the same biological effect, because its serum concentration is 1000 times lower than needed for efficiently capturing and eliminating the circulating AGEs [
30]. Moreover, engagement of RAGE with its ligand has been shown to promote the RAGE shedding [
30,
31]. These findings suggest that sRAGE level could reflect tissue RAGE expression and that AGEs might enhance the cleavage of DPP-4 from the cell membrane. Given the facts that serum DPP-4 activity is largely associated with circulating DPP-4 levels [
10,
32] and that 20% of incretins derived from gastrointestinal tract are still alive in the blood pool [
33,
34], cumulative hyperglycemia and resultant AGE accumulation might impair the incretins’ effects via elevation of circulating DPP-4 levels, further deteriorating glycemic control and thereby forming a vicious cycle in diabetic subjects. This scenario could support the clinical relevance of blockade of the pathological crosstalk between AGE-RAGE axis and DPP-4 by linagliptin in the treatment with type 2 diabetes.