Zinc Transporter 8 (ZnT8) Expression Is Reduced by Ischemic Insults: A Potential Therapeutic Target to Prevent Ischemic Retinopathy

Abstract

The zinc (Zn++) transporter ZnT8 plays a crucial role in zinc homeostasis. It’s been reported that an acute decrease in ZnT8 levels impairs β cell function and Zn++ homeostasis, which contribute to the pathophysiology of diabetes mellitus (DM). Although ZnT8 expression has been detected in the retinal pigment epithelium (RPE), its expression profile in the retina has yet to be determined. Furthermore, the link between diabetes and ischemic retinopathy is well documented; nevertheless, the molecular mechanism(s) of such link has yet to be defined. Our aims were to; investigate the expression profile of ZnT8 in the retina; address the influence of ischemia on such expression; and evaluate the influence of YC-1; (3-(50-hydroxymethyl-20-furyl)-1-benzyl indazole), a hypoxia inducible factor-1 (HIF-1) inhibitor, on the status of ZnT8 expression. We used real-time RT-PCR, immunohistochemistry, and Western blot in the mouse model of oxygen-induced retinopathy (OIR) and Müller cells to evaluate the effects of ischemia/hypoxia and YC-1 on ZnT8 expression. Our data indicate that ZnT8 was strongly expressed in the outer nuclear layer (ONL), outer plexiform layer (OPL), ganglion cell layer (GCL), and nerve fiber layer (NFL), whereas the photoreceptor layer (PRL), inner nuclear layer (INL) and inner plexiform layer (IPL) showed moderate ZnT8 immunoreactivity. Furthermore, we demonstrate that retinal ischemic insult induces a significant downregulation of ZnT8 at the message and protein levels, YC-1 rescues the injured retina by restoring the ZnT8 to its basal homeostatic levels in the neovascular retinas. Our data indicate that ischemic retinopathy maybe mediated by aberrant Zn++ homeostasis caused by ZnT8 downregulation, whereas YC-1 plays a neuroprotective role against ischemic insult. Therefore, targeting ZnT8 provides a therapeutic strategy to combat neovascular eye diseases.

Detection of Serum Antibodies Cross-Reacting with Mycobacterium avium Subspecies paratuberculosis and Beta-Cell Antigen Zinc Transporter 8 Homologous Peptides in Patients with High-Risk Proliferative Diabetic Retinopathy

“…Recently, dysregulation in Zn++ homeostasis caused by ZnT8 downregulation has been implicated in the pathogenesis of ischemic retinopathy [6]. Therefore, it is theoretically possible that ZnT8 downregulation might also be involved in the pathogenesis of PDR, because retinal ischemia caused by capillary occlusion is an essential step in the development of this vision-threatening vascular disorder.…”

SLC30A8 Nonsynonymous Variant Is Associated With Recovery Following Exercise and Skeletal Muscle Size and Strength

“…The SLC30A8 gene encodes a zinc transporter expressed solely in the secretory vesicles of b-cells and is implicated in the final stages of insulin biosynthesis involving cocrystallization with zinc (20). The communication between skeletal muscle and b-cells is thought to contribute to healthy skeletal muscle function and mass (21).…”

Do post-translational beta cell protein modifications trigger type 1 diabetes?

“…Of the established autoantigens in type 1 diabetes, insulin might be the only one that is exclusively expressed in beta cells [9][10][11][12]. The current paradigm of type 1 diabetes as a bona fide autoimmune disease therefore contains a paradox since the beta cell-specific destruction in type 1 diabetes cannot be explained by an immune response against the currently known antigens.…”

“…GAD 65 kDa (GAD65), insulin, protein tyrosine phosphatase (IA-2), zinc transporter 8 (ZnT8) and several additional proteins have been identified as autoantigens based on antibody or T cell reactivity in sera from type 1 diabetes patients [7,8]. However, the paradigm of type 1 diabetes as a classical autoimmune disorder contains a paradox: none of the established autoantigens [9][10][11][12], with the possible exception of insulin, are exclusively expressed in the beta cells, thus failing to explain the selective immunemediated destruction of the beta cells-a fact that has been largely neglected by researchers in the field.…”