Advanced glycation end products delay corneal epithelial wound healing through reactive oxygen species generation
- 557 Downloads
Delayed healing of corneal epithelial wounds is a serious complication in diabetes. Advanced glycation end products (AGEs) are intimately associated with the diabetic complications and are deleterious to the wound healing process. However, the effect of AGEs on corneal epithelial wound healing has not yet been evaluated. In the present study, we investigated the effect of AGE-modified bovine serum albumin (BSA) on corneal epithelial wound healing and its underlying mechanisms. Our data showed that AGE-BSA significantly increased the generation of intracellular ROS in telomerase-immortalized human corneal epithelial cells. However, the generation of intracellular ROS was completely inhibited by antioxidant N-acetylcysteine (NAC), anti-receptor of AGEs (RAGE) antibodies, or the inhibitor of NADPH oxidase. Moreover, AGE-BSA increased NADPH oxidase activity and protein expression of NADPH oxidase subunits, p22phox and Nox4, but anti-RAGE antibodies eliminated these effects. Furthermore, prevention of intracellular ROS generation using NAC or anti-RAGE antibodies rescued AGE-BSA-delayed epithelial wound healing in porcine corneal organ culture. In conclusion, our results demonstrated that AGE-BSA impaired corneal epithelial wound healing ex vivo. AGE-BSA increased intracellular ROS generation through NADPH oxidase activation, which accounted for the delayed corneal epithelial wound healing. These results may provide better insights for understanding the mechanism of delayed healing of corneal epithelial wounds in diabetes.
KeywordsAGEs ROS NADPH oxidase Cornea Wound healing
The authors thank Dr. Edward C. Mignot at the University of Shandong for linguistic advice. This work was supported by the Education Ministry Fund of China (No. 20070422081) and the Graduate Independent Innovation Foundation of Shandong University (No. 21300072613147).
- 12.Niiya Y, Abumiya T, Yamagishi S, Takino J, Takeuchi M (2012) Advanced glycation end products increase permeability of brain microvascular endothelial cells through reactive oxygen species-induced vascular endothelial growth factor expression. J Stroke Cerebrovasc Dis 21:293–298PubMedCrossRefGoogle Scholar
- 21.Kamioka M, Ishibashi T, Ohkawara H, Nagai R, Sugimoto K, Uekita H, Matsui T, Yamagishi S, Ando K, Sakamoto T, Sakamoto N, Takuwa Y, Wada I, Shiomi M, Maruyama Y, Takeishi Y (2011) Involvement of membrane type 1-matrix metalloproteinase (MT1-MMP) in RAGE activation signaling pathways. J Cell Physiol 226:1554–1563PubMedCrossRefGoogle Scholar
- 22.Rodino-Janeiro BK, Gonzalez-Peteiro M, Ucieda-Somoza R, Gonzalez-Juanatey JR, Alvarez E (2010) Glycated albumin, a precursor of advanced glycation end-products, up-regulates NADPH oxidase and enhances oxidative stress in human endothelial cells: molecular correlate of diabetic vasculopathy. Diabetes Metab Res Rev 26:550–558PubMedCrossRefGoogle Scholar