Eicosanoids and Oxidative Stress in Diabetic Retinopathy

Abstract

Oxidative stress is an important factor to cause the pathogenesis of diabetic retinopathy (DR) because the retina has high vascularization and long-time light exposition. Cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) enzymes can convert arachidonic acid (AA) into eicosanoids, which are important lipid mediators to regulate DR development. COX-derived metabolites appear to be significant factors causative to oxidative stress and retinal microvascular dysfunction. Several elegant studies have unraveled the importance of LOX-derived eicosanoids, including LTs and HETEs, to oxidative stress and retinal microvascular dysfunction. The role of CYP eicosanoids in DR is yet to be explored. There is clear evidence that CYP-derived epoxyeicosatrienoic acids (EETs) have detrimental effects on the retina. Our recent study showed that the renin-angiotensin system (RAS) activation augments retinal soluble epoxide hydrolase (sEH), a crucial enzyme degrading EETs. Our findings suggest that EETs blockade can enhance the ability of RAS blockade to prevent or mitigate microvascular damage in DR. This review will focus on the critical information related the function of these eicosanoids in the retina, the interaction between eicosanoids and reactive oxygen species (ROS), and the involvement of eicosanoids in DR. We also identify potential targets for the treatment of DR.

Keywords: Cytochrome P450; cyclooxygenase; diabetic retinopathy; eicosanoids; lipoxygenase; oxidative stress.

Figure 1

Bioactive eicosanoids derived from arachidonic acid (AA) cascade. After trigging by inflammatory conditions such as the presence of cytokines and growth factors, AA-containing phospholipids are hydrolyzed by phospholipase A2 (PLA2), resulting in the release of free AA. AA can be further metabolized by three pathways, i.e., the cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) pathways. AA cascade generates prostaglandins (PGs), thromboxane A2 (TXA2), and a series of hydroxyeicosatetraenoic acids (HETEs), leukotrienes (LTs), and epoxyeicosatrienoic acids (EETs).

Figure 2

(A) EET receptor (GPR40) protein is expressed in the retina and human retinal endothelial cells (HRECs). The samples from the pancreas were used as a positive control. (B) GPR40 (red) and IB4 (green; a marker of the retinal blood vessel) in the retina. The retinal and pancreatic samples were isolated from male mice.

Figure 3

(A) Retinal section, which was isolated from mice, stained with hematoxylin and eosin showing different retinal layers as seen under the microscope from inside to outside are the ganglion cell (GC), inner plexiform (IPL), inner nuclear (INL), outer plexiform (OPL), outer nuclear (ONL), and retinal pigment epithelium (RPE). (B) Immunostaining of retinal section (mouse) with the vascular marker (isolectin-B4, red) and nuclear marker (DAPI, blue), showing that retinal blood vessels (inside the white box) are primarily localized in the inner retinal layers (the nerve fiber and ganglion cell layer and plexiform layer). The arrow in B is pointing to inner retinal layers that contain blood vessels (red).

Figure 4

Cascade events involved in the pathogenesis of DR: Hyperglycemia activates the PLA2 to release AA from the retinal cell membrane. AA is converted to 12- or 15-HETE that generates ROS through NOX, creating a status of oxidative stress. This oxidative stress leads to the activation of retinal endothelial cells through various inflammatory signaling pathways, leading to leukocyte adhesion, hyperpermeability, and ultimately NV (the cardinal signs of DR).

Figure 5

The hypothesis about the interaction of sEH/EETs and RAS in DR. During diabetes, RAS activation augments retinal sEH, via AT1, which decreases EETs (pro-permeability and pro-angiogenesis factors) to counterbalance the effects of RAS on retinal microvascular damage.

Figure 6

General mechanisms for the development of the early stage of DR and proliferative DR. We also indicate the potential therapeutic methods of the eicosanoid pathways to prevent the development of the early stage of DR and proliferative DR.