Abstract
We previously demonstrated that the bile acid taurocholic acid (TCA) inhibits features of age-related macular degeneration (AMD) in vitro. The purpose of this study was to determine if the glycine-conjugated bile acids glycocholic acid (GCA), glycodeoxycholic acid (GDCA), and glycoursodeoxycholic acid (GUDCA) can protect retinal pigment epithelial (RPE) cells against oxidative damage and inhibit vascular endothelial growth factor (VEGF)-induced angiogenesis in choroidal endothelial cells (CECs). Paraquat was used to induce oxidative stress and disrupt tight junctions in HRPEpiC primary human RPE cells. Tight junctions were assessed via transepithelial electrical resistance and ZO-1 immunofluorescence. GCA and GUDCA protected RPE tight junctions against oxidative damage at concentrations of 100–500 µM, and GDCA protected tight junctions at 10–500 µM. Angiogenesis was induced with VEGF in RF/6A macaque CECs and evaluated with cell proliferation, cell migration, and tube formation assays. GCA inhibited VEGF-induced CEC migration at 50–500 µM and tube formation at 10–500 µM. GUDCA inhibited VEGF-induced CEC migration at 100–500 µM and tube formation at 50–500 µM. GDCA had no effect on VEGF-induced angiogenesis. None of the three bile acids significantly inhibited VEGF-induced CEC proliferation. These results suggest glycine-conjugated bile acids may be protective against both atrophic and neovascular AMD.
Highlights
Accepted: 21 April 2021Age-related macular degeneration (AMD) remains a leading cause of irreversible vision loss in older adults, despite currently available treatments
The purpose of the current study was to determine if the glycine-conjugated bile acids glycocholic acid (GCA), glycodeoxycholic acid (GDCA), and glycoursodeoxycholic acid (GUDCA) can protect retinal pigment epithelium (RPE) tight junction integrity against oxidative stress-mediated damage and if they can inhibit vascular endothelial growth factor (VEGF)-induced of angiogenesis in choroidal endothelial cells (CECs)
To determine whether GCA, GDCA, and GUDCA could protect RPE cells against tight junction disruption caused by paraquat-induced oxidative stress, HRPEpiC cells were grown to confluence and treated with 300 μM paraquat to destabilize tight junctions
Summary
Age-related macular degeneration (AMD) remains a leading cause of irreversible vision loss in older adults, despite currently available treatments. In advanced AMD, vision loss results from either geographic atrophy (GA), in which photoreceptors and underlying retinal pigment epithelium (RPE) degenerate, or from neovascular AMD (NVAMD), in which blood or serous fluid leaks from abnormal choroidal vessels. Neovascularization occurs when choroidal endothelial cells (CECs) migrate through the blood retina barrier (BRB), proliferate, and form tubes of new vessels. There is currently no effective treatment for GA, and while intravitreal injections of anti-vascular endothelial growth factor (antiVEGF) medications are routinely used to treat NVAMD, they are expensive, and the need for ongoing treatment is a significant burden on patients. Bile acids have been shown to exert beneficial effects in experimental models of retinal diseases. Primary and secondary bile acids are both commonly conjugated to glycine or taurine in the liver.
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