Effects of intravitreal injection of KH902, a vascular endothelial growth factor receptor decoy, on the retinas of streptozotocin‐induced diabetic rats

Abstract

KH902 is a fusion protein that can bind vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) through its binding ligand taken from the domains of VEGF receptor 1 and VEGF receptor 2 (VEGFR2). This study was to investigate the effects of intravitreal injection of KH902 on the retinas of streptozotocin-induced diabetic rats. Two weeks after induction of diabetes, the left eyes of diabetic rats in each group received an intravitreal injection of phosphate-buffered saline (PBS), Avastin or KH902 solution, respectively. Four weeks after intravitreal injection, retinal electrophysiological function and the integrity of inner blood retinal barrier (iBRB) were measured by electroretinogram and Evans blue perfusion. The protein levels of VEGF signal pathway were assayed by western blot. The expression and distribution of claudin-5 and occludin were analysed by double immunofluorescent staining under confocal microscope. The expression of VEGFR2 and PlGF was measured by immunohistochemistry. Four weeks after intravitreal injection, KH902-treated rats had better retinal electrophysiological function, less retinal vessel leakage and lower levels of VEGFR2, PI3K, AKT, p-AKT, p-ERK and p-SRC than PBS or Avastin-treated rats. The distribution of claudin-5 and occludin in the retinal vessels of diabetic rats treated by KH902 was smoother and more uniform than those of diabetic rats treated by PBS or Avastin. The expression of PlGF and VEGFR2 in KH902-treated rats was decreased compared with those in PBS or Avastin-treated rats. KH902 could improve retinal electrophysiological function and inhibit the breakdown of iBRB by inhibiting the expression of VEGFR2, PlGF and PI3K, and the activation of SRC, AKT and ERK.