Effects of High Glucose-Induced Lysyl Oxidase Propeptide on Retinal Endothelial Cell Survival: Implications for Diabetic Retinopathy

Abstract

Diabetic retinopathy (DR) is characterized by apoptotic cell loss in the retinal vasculature. Lysyl oxidase propeptide (LOX-PP), released during LOX processing, has been implicated in promoting apoptosis in various diseased tissues. However, its role in the development and progression of DR is unknown. We investigated whether high glucose (HG) or diabetes alters LOX-PP expression and thereby influences AKT pathway and affects retinal endothelial cell survival. Rat retinal endothelial cells were grown in normal medium, normal medium and exposed to recombinant LOX-PP (rLOX-PP) or HG medium and examined for LOX-PP expression, AKT and caspase-3 activation. Similarly, rats intravitreally injected with rLOX-PP were examined for changes in retinal LOX-PP levels, AKT phosphorylation, and the number of acellular capillaries and pericyte loss compared with those of control diabetic and nondiabetic rats. Results indicate that HG up-regulates LOX-PP expression and reduces AKT activation. In addition, cells exposed to rLOX-PP alone exhibited increased apoptosis concomitant with decreased AKT phosphorylation. In retinas of diabetic rats, increased LOX-PP level, decreased AKT phosphorylation, and increased number of acellular capillaries and pericyte loss compared with those of nondiabetic rats were observed. Of interest, similar changes were noted in the retinas of rats injected with rLOX-PP. Findings from this study suggest that hyperglycemia-induced LOX-PP overexpression may contribute to retinal vascular cell loss associated with DR.