Inflammation in the early pathogenesis of diabetic retinopathy

Abstract

Introduction – Diabetes is a growing health concern. Diabetic retinopathy (DR), is a complication resulting from long-term diabetes and is currently the leading cause of blindness in the US. The cause of pericyte loss, an early indiciator of DR progression, is currently unknown. Inflammation, increased in diabetes, could play a role in the progression of DR and be one of the causes of pericyte loss. Methods and Materials- Retinas from 3, 6, 12, 18, and 24 week Akita (AK) and DB mice were taken and cell counts, vasculature, and mRNA expression were examined. Pericytes treated with IFN-γ and PDGF-BB in chronic and acute conditions and PDGFRβ signaling was determined using Western blot analysis. Apoptosis and proliferation were examined using western blots and immunohistochemistry of IFN-γ treated pericytes. Results- Pericytes numbers were changed as 3 weeks in DB and Akita models. Proinflammatory markers increased at 6 weeks and displayed their maximum expression at 12 and 18 weeks. Chronic treatments with IFN-γ changed AKT and PKCδ activation and increases pericytes apoptosis. Discussion- Pericyte loss appears to begin prior to an increase in pro-inflammatory factors indicating that perhaps retinal inflammtion may not initiate pericyte loss or that loss of pericyte numbers at 3 weeks may be due to reduced numbers of neural crest cells migrating to vasculature or a reduced number of neural crest cells differentiating into pericytes. Proinflammatory changes occur between 3-6 weeks in both Akita and DB models of diabetes; however, the peak levels in expression of proinflammtory markers differs between Akita and DB models. One of the markers that increased very early in the progression of diabetic retinopathy, IFN-γ, triggered apoptosis in isolated retinal pericytes by increasing protein kinase Cδ activation, which then reduced activity of AKT.