Kangwon National University School of Medicine, Gangwon-do 200-701, Korea
Kwon-Soo Ha has completed his PhD in 1991 from the University of Texas at Austin and postdoctoral studies from Vanderbilt University School of Medicine. He is the director of the Institute of of Medical Science, Kangwon National University School of Medicine, Korea. He is also the principal investigator of Vascular Network Convergence Research Lab Program supported by the Korea Research Foundation. He has published 185 papers in peer reviewed international journals. His research interests are prevention of diabetic complications including retinopathy, cardiovascular diseases, and impaired wound healing and applications of protein arrays to serodiagnosis.
Diabetic retinopathy is predominantly caused by vascular endothelial growth factor (VEGF)-induced microvascular leakage; however, the underlying mechanism is unclear. Here, we demonstrated that hyperglycemia induced microvascular leakage by activating TGase2 and this vascular leakage was inhibited by C-peptide in diabetic retina. VEGF elevated TGase2 activity through sequential elevation of intracellular Ca2+ and reactive oxygen species (ROS) levels in endothelial cells. The TGase inhibitors cystamine and monodancylcadaverin or TGase2 siRNA prevented VEGF-induced stress fiber formation and vascular endothelial (VE)-cadherin disruption, which play a critical role in modulating endothelial permeability. C-peptide inhibited the VEGF-induced ROS generation, stress fiber formation, and disassembly of vascular endothelial cadherin in endothelial cells. Intravitreal injection of C-peptide, two TGase inhibitors, or TGase2 siRNA successfully inhibited hyperglycemia-induced TGase activation and microvascular leakage in the retinas of diabetic mice. Thus, our findings suggest that C-peptide prevents VEGF-induced microvascular permeability by inhibiting ROS-mediated activation of TG2 in diabetic mice.