Canonical Wnt signaling in diabetic retinopathy

Abstract

Diabetic retinopathy (DR) is a common eye complication of diabetes, and the pathogenic mechanism of DR is still under investigation. The canonical Wnt signaling pathway is an evolutionarily conserved pathway that plays fundamental roles in embryogenesis and adult tissue homeostasis. Wnt signaling regulates expression of multiple genes that control retinal development and eye organogenesis, and dysregulated Wnt signaling plays pathophysiological roles in many ocular diseases, including DR. This review highlights recent progress in studies of Wnt signaling in DR. We discuss Wnt signaling regulation in the retina and dysregulation of Wnt signaling associated with ocular diseases with an emphasis on DR. We also discuss the therapeutic potential of modulating Wnt signaling in DR. Continued studies in this field will advance our current understanding on DR and contribute to the development of new treatments.

Keywords: Angiogenesis; Diabetes; Inflammation; Oxidative stress; Retinopathy; Wnt signaling.

Fig. 1.

The canonical Wnt signaling pathway. (A) In the absence of Wnt, β-catenin (β-cat) interacts with the destruction complex formed by a scaffold protein Axin, casein kinase Iα (CKIα) and glycogen synthase kinase 3 beta (GSK-3b) as well as adenomatous polyposis coli (APC), and is constitutively phosphorylated and degraded. (B) In the presence of Wnt, Wnt binds to frizzled receptor (Fzd) and co-receptor low-density lipoprotein receptor-related protein 5 or 6 (LRP5/6). LPR5/6 is phosphorylated, which leads to the recruitment and phosphorylation of Dishevelled (Dvl). Subsequently, Axin is recruited to the receptor complex and the destruction complex is disassembled, blocking the phosphorylation of soluble cytoplasmic β-cat. β-cat is then stabilized and translocates to the nucleus to activate transcription of target genes.

Fig. 2.

Over-activated canonical Wnt signaling in DR and potential therapeutic inhibitors of canonical Wnt signaling for DR. In diabetic conditions, hyperglycemia induces the up-regulation of Wnt signaling in the retina. Levels of Wnt signaling components, low-density lipoprotein receptor-related protein 6 (LRP6), Frizzled 7 and β-catenin are up-regulated, and the Wnt signaling downstream target genes are over-expressed, which results in angiogenesis, inflammation and increased oxidative stress in diabetic retina and leads to DR. Wnt signaling inhibitors with therapeutic potential – SERPINA3K: Serine proteinase inhibitors 3K, PEDF: Pigment epithelium-derived factor, VLDLR: very low-density lipoprotein receptor, DKK1: dickkopf-related protein 1. Mab2F1: an anti-LRP6 monoclonal antibody which was generated in our laboratory.