TGF-β Signaling Pathways in the Development of Diabetic Retinopathy

Abstract

Diabetic retinopathy (DR), a prevalent complication of diabetes mellitus affecting a significant portion of the global population, has long been viewed primarily as a microvascular disorder. However, emerging evidence suggests that it should be redefined as a neurovascular disease with multifaceted pathogenesis rooted in oxidative stress and advanced glycation end products. The transforming growth factor-β (TGF-β) signaling family has emerged as a major contributor to DR pathogenesis due to its pivotal role in retinal vascular homeostasis, endothelial cell barrier function, and pericyte differentiation. However, the precise roles of TGF-β signaling in DR remain incompletely understood, with conflicting reports on its impact in different stages of the disease. Additionally, the BMP subfamily within the TGF-β superfamily introduces further complexity, with BMPs exhibiting both pro- and anti-angiogenic properties. Furthermore, TGF-β signaling extends beyond the vascular realm, encompassing immune regulation, neuronal survival, and maintenance. The intricate interactions between TGF-β and reactive oxygen species (ROS), non-coding RNAs, and inflammatory mediators have been implicated in the pathogenesis of DR. This review delves into the complex web of signaling pathways orchestrated by the TGF-β superfamily and their involvement in DR. A comprehensive understanding of these pathways may hold the key to developing targeted therapies to halt or mitigate the progression of DR and its devastating consequences.

Keywords: TGF-β; bone morphogenic proteins; cell signaling; diabetes mellitus; diabetic retinopathy; reactive oxygen species; retina; transforming growth factor-β.

Figure 1

Summary of the current understanding of TGF-β roles in diabetic retinopathy. TGF-β is understood to be pervasively crucial to retinal homeostasis and is closely associated with the pathogenesis of diabetic retinopathy across multiple cell types and interactions. However, the precise action of each TGF-β superfamily member remains largely unclear. Diabetic complications encompass the myriad of destructive mechanisms that contribute to diabetic retinopathy, like hyperglycemia and immune response. Positive associations are denoted by the arrowhead (↓), and negative associations are denoted by the inhibitory arrow (I). Abbreviations are as follows: TGF = transforming growth factor; VEGF = vascular endothelial growth factor; BMP = bone morphogenic growth factor; BMPER = bone morphogenic protein endothelial receptor; FOXP3 = forkhead box protein 3; Treg = regulatory T-cell.