Thioredoxin Interacting Protein (TXNIP) and Pathogenesis of Diabetic Retinopathy

Lalit P Singh

doi:10.4172/2155-9570.1000287

Abstract

Chronic hyperglycemia (HG)-associated reactive oxygen/nitrogen species (ROS/RNS) stress and low grade inflammation are considered to play critical roles in the development of diabetic retinopathy (DR). Excess glucose metabolic flux through the aldose reductase/polyol pathway, advanced glycation end product (AGE) formation, elevated hexosamine biosynthesis pathway (HBP), diacyl glycerol/PKC activation, and mitochondrial ROS generation are all implicated in DR. In addition, endoplasmic reticulum stress/unfolded protein response (er-UPR) and deregulation of mitochondrial quality control by autophagy/mitophagy are observed causing cellular bioenergetic deficiency and injury. Recently, a pro-oxidant and pro-apoptotic thioredoxin interacting protein (TXNIP) was shown to be highly upregulated in DR and by HG in retinal cells in culture. TXNIP binds to thioredoxin (Trx) inhibiting its oxidant scavenging and thiolreducing capacity. Hence, prolonged overexpression of TXNIP causes ROS/RNS stress, mitochondrial dysfunction, inflammation and premature cell death in DR. Initially, DR was considered as microvascular complications of endothelial dysfunction and pericyte loss characterized by capillary basement membrane thickening, pericyte ghost, blood retinal barrier leakage, acellular capillary and neovascularization. However, it is currently acknowledged that neuro-glia are also affected by HG in diabetes and that neuronal injury, glial activation, innate immunity/sterile inflammation, and ganglion apoptosis occur early in DR. In addition, retinal pigment epithelium (RPE) becomes dysfunctional in DR. Since TXNIP is induced by HG in most cells, its effects are not restricted to a particular cell type in DR. However, depending on the metabolic activity and anti-oxidant capacity, some cells may be affected earlier by TXNIP than others. Identification of TXNIP sensitive cells and elucidating the underlying mechanism(s) will be critical for preventing pre-mature cell death and progression of DR.

Highlights

Retinal ArchitectureRetina is a part of the central nervous system (CNS) responsible for visual perception and processing [1,2]
thioredoxin interacting protein (TXNIP) is upregulated in most retinal cells, TXNIP may function in different ways including regulation of plasma membrane receptor signaling, glucose uptake, nuclear gene expression and cell cycle control, cytosolic ER-stress and MT-stress responses, and TXNIP is critically involved in bioenergetics, inflammation and apoptosis [38,58,59,112]
As hyperglycemia prevails in prediabetes/diabetes, the MT aerobic respiration will be enhanced via oxidative phosphorylation (OxPhoS) and ATP synthesis in the MT inner membrane electron transfer chain (ETC)

Summary

Introduction

Retinal ArchitectureRetina is a part of the central nervous system (CNS) responsible for visual perception and processing [1,2]. An injury to blood vessel or neuron leads to glial activation, including Muller cell and microglia, and induces altered neurotrophic and pro-inflammatory gene expression. By trapping Trx, TXNIP causes cellular oxidative stress and apoptosis in different cell types in diabetes and under HG, especially of pancreatic beta cells, which is critical for insulin production.

Results

Conclusion