Ascorbic acid repletion: A possible therapy for diabetic macular edema?

Abstract

Macular edema poses a significant risk for visual loss in persons with diabetic retinopathy. It occurs when plasma constituents and fluid leak out of damaged retinal microvasculature in the area of the macula, causing loss of central vision. Apoptotic loss of pericytes surrounding capillaries is perhaps the earliest feature of diabetic vascular damage in the macula, which is also associated with dysfunction of the endothelium and loss of the otherwise very tight endothelial permeability barrier. Increased oxidative stress is a key feature of damage to both cell types, mediated by excess superoxide from glucose-induced increases in mitochondrial metabolism, as well as by activation of the receptor for advanced glycation end products (RAGE). The latter in turn activates multiple pathways, some of which lead to increased oxidative stress, such as those involving NF-ĸB, NADPH oxidase, and endothelial nitric oxide synthase. Such cellular oxidative stress is associated with low cellular and plasma ascorbic acid levels in many subjects with diabetes in poor glycemic control. Whether repletion of low ascorbate in retinal endothelium and pericytes might help to prevent diabetic macular edema is unknown. However, cell culture studies show that the vitamin prevents high-glucose and RAGE-induced apoptosis in both cell types, that it preserves nitric oxide generated by endothelial cells, and that it tightens the leaky endothelial permeability barrier. Although these findings need to be confirmed in pre-clinical animal studies, it is worth considering clinical trials to determine whether adequate ascorbate repletion is possible and whether it might help to delay or even reverse early diabetic macular edema.

Keywords: Ascorbate; Diabetes; Endothelial cells; Macular edema; Pericytes.

Figure 1

Pericyte and endothelial anatomy.

Figure 2

Sources of oxidative stress induced by RAGE activation in endothelial cells. RAGE activation enhances the synthesis and translocation of NF-κB by multiple mechanisms. It also activates NOX to generate superoxide (O^2•–), which further activates NF-κB via RAS and the phosphoinositide 3-kinase and Akt pathways. Superoxide is also generated as a by-product of increase mitochondrial metabolism due to high intracellular glucose concentrations. Downstream products of superoxide damage cellular proteins, lipids, and DNA. For example, reaction of superoxide with NO generated by eNOS forms peroxynitrite, which is a powerful oxidizing and nitrating agent. Abbreviations not defined in the text: Akt, protein kinase B; EPO, erythropoietin; ERK1/2, extracellular-regulated-kinase1/2; IL, interleukin; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; PDGF-β, platelet-derived growth factor- β; PKC, protein kinase C; rac1, Ras-related C3 botulinum toxin substrate 1; TGF- β, transforming growth factor- α; TNF- α; tumor necrosis factor- α.

Figure 3

Mechanisms by which ascorbate (AA) decreases oxidative stress in endothelial cells. Ascorbate enters endothelial cells and pericytes on the SVCT2 (Sodium-dependent Vitamin C Transporter-2) and likely achieves low millimolar levels in both cell types. At this concentration, it preserves NO by recycling tetrahydrobiopterin in eNOS, as well as by reducing superoxide to H₂O₂, which is then destroyed by catalase. Removal of superoxide decreases RAS-mediated activation of NF-κB, as well as formation of peroxynitrite, which is also scavenged by ascorbate. Ascorbate also decreases translocation of NF-κB to the nucleus and inactivates HIF-1α.