The Role of Lipoxidation in the Pathogenesis of Diabetic Retinopathy

Abstract

Lipids can undergo modification as a result of interaction with reactive oxygen species (ROS). For example, lipid peroxidation results in the production of a wide variety of highly reactive aldehyde species which can drive a range of disease-relevant responses in cells and tissues. Such lipid aldehydes react with nucleophilic groups on macromolecules including phospholipids, nucleic acids, and proteins which, in turn, leads to the formation of reversible or irreversible adducts known as advanced lipoxidation end products (ALEs). In the setting of diabetes, lipid peroxidation and ALE formation has been implicated in the pathogenesis of macro- and microvascular complications. As the most common diabetic complication, retinopathy is one of the leading causes of vision loss and blindness worldwide. Herein, we discuss diabetic retinopathy (DR) as a disease entity and review the current knowledge and experimental data supporting a role for lipid peroxidation and ALE formation in the onset and development of this condition. Potential therapeutic approaches to prevent lipid peroxidation and lipoxidation reactions in the diabetic retina are also considered, including the use of antioxidants, lipid aldehyde scavenging agents and pharmacological and gene therapy approaches for boosting endogenous aldehyde detoxification systems. It is concluded that further research in this area could lead to new strategies to halt the progression of DR before irreversible retinal damage and sight-threatening complications occur.

Keywords: advanced lipoxidation end products; aldehydes; detoxification; diabetes; lipid peroxidation; oxidative stress; polyunsaturated fatty acids; retina.

Figure 1

Schematic representation of neuronal and vascular structure in the healthy and diabetic retina. The healthy retina comprises of glial elements including Müller cells and astrocytes, neuronal elements including photoreceptors, ganglion, amacrine and bipolar cells, resting microglia and healthy retinal blood vessels. In contrast, the diabetic retina exhibits multiple abnormalities such as Müller cell swelling, neuronal damage, activated microglia and vascular changes (pericyte dropout, hemorrhage and neovascularization). Dysfunction of the iBRB results in the accumulation of fluid. Created with BioRender (https://app.biorender.com).

Figure 2

Schematic representation of lipid peroxidation and the formation of lipid aldehydes. The chemical structure of docosahexaenoic acid (DHA) is used to represent a lipid (L) undergoing peroxidation (1). Lipids (L) can become radicalized to form an alkyl radical (L^•) (2) by some initiating radical species, (R^•), (e.g. reactive oxygen species (ROS) via oxidative stress or other lipid peroxidation-derived radical molecules (L^•, LOO^•, etc.)) by abstracting a hydrogen from a lipid’s allylic carbon. Alkyl radicals can reversibly rearrange to form conjugated dienes (3), resulting in a higher susceptibility to oxygenation, forming a lipid peroxyl radical (LOO^•) (4). Lipid peroxyl radicals will then accept hydrogen from any number of sources, forming lipid hydroperoxide (LOOH) (5). Abstracting another lipid’s allylic hydrogen leads to a propagation of the prior reaction in other lipids (2–5). LOOHs and PUFAs degrade to form lipid aldehydes under a plethora of mechanisms, both non-enzymatic and enzymatic. Abbreviations: polyunsaturated fatty acid (PUFA), lipid (L), lipid radical (e.g. alkyl radical/conjugated diene radical) (L^•), lipid peroxyl radical (LOO^•), lipid hydroperoxide (LOOH), acrolein (ACR), 4-hydroxy-2-nonenal (4-HNE), malondialdehyde (MDA), glyoxal (GO), 4-hydroxy-2-hexenal (4-HHE) 4-oxo-2-nonenal (4-ONE), spermine oxidase (SMOX), acetylpolyamine oxidase (APAO), cyclooxygenase (COX), prostacyclin synthase (PTGS), thromboxane synthase (TXA), lipoxygenase (LOX), hydroperoxide lyase (HPL), alkenal oxygenase (AKO), peroxygenase (PO).

Figure 3

Representative confocal images showing FDP-Lys immunoreactivity (green) in transverse retinal cryosections from a non-diabetic and STZ-diabetic rat of 4-months disease duration. Nuclei were counterstained with propidium iodide nuclear stain (red). In the diabetic animal, a marked accumulation of FDP-Lys was observed in the Müller glia radial fibers and neurons of the inner retina. ONL, Outer Nuclear Layer; INL, Inner Nuclear Layer; GCL, Ganglion Cell Layer.

Figure 4

Schematic diagram showing the central role of Müller glia FDP-Lys accumulation in the pathogenesis of DR. FDP-Lys accumulation in Müller glia induces increased oxidative stress, the release of angiogenic and inflammatory factors, dysregulation of retinal K⁺ transport, and apoptosis in the diabetic retina which contributes to the sight-threatening complications of DR. Created with BioRender (https://app.biorender.com).