Elucidating the mechanism of action of alpha-1-antitrypsin using retinal pigment epithelium cells exposed to high glucose. Potential use in diabetic retinopathy

Abstract

Background Alpha-1-antitrypsin is a protein involved in avoidance of different processes that are seen in diabetic retinopathy pathogenesis. These processes include apoptosis, extracellular matrix remodeling and damage of vessel walls and capillaries. Furthermore, because of its antiinflammatory effects, alpha-1-antitrypsin has been proposed as a possible therapeutic approach for diabetic retinopathy. Our group tested alpha-1-antitrypsin in a type 1 diabetes mouse model and observed a reduction of inflammation and retinal neurodegeneration. Thus, shedding light on the mechanism of action of alpha-1-antitrypsin at molecular level may explain how it works in the diabetic retinopathy context and show its potential for use in other retinal diseases. Methods In this work, we evaluated alpha-1-antitrypsin in an ARPE-19 human cell line exposed to high glucose. We explored the expression of different mediators on signaling pathways related to pro-inflammatory cytokines production, glucose metabolism, epithelial-mesenchymal transition and other proteins involved in the normal function of retinal pigment epithelium by RT-qPCR and Western Blot. Results We obtained different expression patterns for evaluated mediators altered with high glucose exposure and corrected with the use of alpha-1-antitrypsin.

Mechanisms behind Retinal Ganglion Cell Loss in Diabetes and Therapeutic Approach

“…Furthermore, in a recent publication made by our group, we elucidated some of the molecular mechanisms behind A1AT treatment in an in vitro study of RPE cells exposed to high glucose. Some of the pathways modulated by A1AT treatment are altered with diabetic retinopathy affecting RGCs, like mTOR, Akt and NFkB [176]. It is worth mentioned that these pathways modulated by A1AT in RPE cells are in also in accordance with results of investigations carried out in non-ocular tissues which are described in the following paragraphs.…”

Recent Developments in Diabetic Retinal Neurodegeneration: A Literature Review

“…Several novel therapeutic approaches of DRN have been applied recently. Promising results have been obtained in experimental models of DRN with anti-inflammatory agents, such as alpha-1-antitrypsin (A1AT) [ 85 – 87 ], citicoline [ 88 , 89 ], epigallocatechin-3-gallate (EGCG) [ 135 – 137 ]. Intravitreal fluocinolone acetonide, used to treat patients with diabetic macular edema, achieved a positive effect on the inhibition of DRN [ 90 ].…”

“…In an attempt to elucidate A1AT's mechanism of action on a molecular level, it was later studied in ARPE-19 cells exposed to high glucose. A1AT normalized the levels of NF κ B and its targets iNOS and TNF- α , as well as regulated proteins related to glucose metabolism, awakened signals related to epithelial-mesenchymal transition, and normalized protein levels involved in essential RPE function [ 87 ].…”

Alpha‐1‐antitrypsin reduces inflammation and exerts chondroprotection in arthritis

“…Serpins, including AAT, have been reported to modulate Wnt signaling [31][32][33] in various cell types. Using the Wnt reporter assay TOPFlash, we discovered that AAT potently inhibited the capacity of Wnt3A to induce β-catenin accumulation in chondrocytes, even in a polymerized F I G U R E 2 Gene expression profiles of arthritic paws and plasma cytokine levels before and after systemic administration of AAT.…”