Abstract
Advanced glycation end products (AGEs) are associated with the pathogenesis of diabetic vascular complications. Induction of the endothelial-to-mesenchymal transition (EndMT) is associated with the pathogenesis of fibrotic diseases. The roles of AGEs in islet EndMT induction and diabetes-related islet microvasculopathy and fibrosis remain unclear. This study investigated the pathological roles of AGEs in islet EndMT induction and fibrosis in vitro and in vivo. Non-cytotoxic concentrations of AGEs upregulated the protein expression of fibronectin, vimentin, and α-smooth muscle actin (α-SMA) (mesenchymal/myofibroblast markers) and downregulated the protein expression of vascular endothelial (VE)-cadherin and cluster of differentiation (CD) 31 (endothelial cell markers) in cultured mouse pancreatic islet endothelial cells, which was prevented by the AGE cross-link breaker alagebrium chloride. In streptozotocin-induced diabetic mice, the average islet area and islet immunoreactivities for insulin and CD31 were decreased and the islet immunoreactivities for AGEs and α-SMA and fibrosis were increased, which were prevented by the AGE inhibitor aminoguanidine. Immunofluorescence double staining showed that α-SMA-positive staining co-localized with CD31-positive staining in the diabetic islets, which was effectively prevented by aminoguanidine. These results demonstrate that AGEs can induce EndMT in islet endothelial cells and islet fibrosis in diabetic mice, suggesting that AGE-induced EndMT may contribute to islet fibrosis in diabetes.