Vitamin-D3 (α-1, 25(OH) 2D3) Protects Retinal Pigment Epithelium From Hyperoxic Insults

Abstract

Citation: Murugeswari P, Firoz A, Murali S, et al. Vitamin-D3 (α-1, 25(OH) 2D3) protects retinal pigment epithelium from hyperoxic insults. Invest Ophthalmol Vis Sci. 2020;61(2):4. https://doi.org/10.1167/iovs.61.2.4 PURPOSE.Oxidative stress affects the retinal pigment epithelium (RPE) leading to development of vascular eye diseases. Cholecalciferol (VIT-D) is a known modulator of oxidative stress and angiogenesis. This in vitro study was carried out to evaluate the protective role of VIT-D on RPE cells incubated under hyperoxic conditions. METHODS.Cadaver primary RPE (PRPE) cells were cultured in hyperoxia (40% O 2 ) with or without VIT-D (α-1, 25(OH) 2D3). The functional and physiological effects of PRPE cells with VIT-D treatment were analyzed using molecular and biochemical tools. RESULTS.Vascular signaling modulators, such as vascular endothelial growth factor (VEGF) and Notch, were reduced in hyperoxic conditions but significantly upregulated in the presence of VIT-D. Additionally, PRPE conditioned medium with VIT-D induced the tubulogenesis in primary human umbilical vein endothelial cells (HUVEC) cells. VIT-D supplementation restored phagocytosis and transmembrane potential in PRPE cells cultured under hyperoxia. CONCLUSIONS. VIT-D protects RPE cells and promotes angiogenesis under hyperoxic insult.These findings may give impetus to the potential of VIT-D as a therapeutic agent in hyperoxia induced retinal vascular diseases.Keywords: retinal pigment epithelium, vitamin D, hyperoxia, vascular endothelial growth factor (VEGF), tubulogenesis O xidative stress is the result of an imbalance between the synthesis of reactive oxygen species (ROS) and the levels of antioxidants in the cells. It plays a major role in the pathophysiology of various ocular diseases, such as agerelated cataract, macular degeneration, glaucoma, diabetic retinopathy, and retinitis pigmentosa, by affecting cellular and vascular physiological aspects. 1,2 Antioxidants, such as enzymatic antioxidants, vitamins, minerals, carotenoids, and flavonoids, are the primary scavengers of ROS reducing levels of oxidative stress. 3 Cholecalciferol (vitamin-D3 (VIT-D)) has diverse functions, including modulation of inflammation, angiogenesis, oxidative stress, and fibrosis. 4,5 Recent studies have demonstrated an association between VIT-D and retinal pathophysiological conditions, such as age-related macular degeneration (AMD), diabetic retinopathy, and retinopathy of prematurity (ROP). 6−8 These studies implicated deficiency of VIT-D to higher risk for early/late AMD, whereas a supplementation leads to delay or prevention in the progression of AMD. 6,9 Although VIT-D receptors as well as enzymes for VIT-D metabolism are present in the retina, choroid, and retinal pigment epithelium (RPE) cells, their functions are still not well understood. 6 VIT-D has been studied as a potential inhibitor of angiogenesis in a mouse model of oxygen-induced ischemic retinopathy (OIR). 10 A correlation of VIT-D and vascular endothelial growth factor (VEGF) has been ob...

Anti-Inflammatory and Anti-Oxidative Synergistic Effect of Vitamin D and Nutritional Complex on Retinal Pigment Epithelial and Endothelial Cell Lines against Age-Related Macular Degeneration

“…Additionally, our results demonstrated that application of N and ND to the media counteracted these morphological changes. Earlier investigations demonstrated that vitamin D restored damaged tight junctions and increased ZO-1 protein levels in ARPE-19 cells under oxidative stress conditions [ 36 , 46 ], which suggests its role in blood–retinal barrier integrity through intercellular adherent junctions [ 47 ].…”

“…In addition, our results demonstrate significant reduction in cell proliferation after addition of H 2 O 2 in both cell lines, characterized by subsequent recovery following application of either N or ND to the media, with ND presenting a more potent effect than N in HREC cells. Earlier studies have effectively described the vital role of oxidative stress by H 2 O 2 in inhibiting cell proliferation in various cells [ 62 ], including RPE in the retina [ 35 , 46 , 63 , 64 ]. The exact mechanisms have not been identified, however, recent studies have revealed the interference of H 2 O 2 in numerous intracellular signaling pathways in retinal epithelial cells, such as the epidermal growth factor receptor/AKT and Notch signaling pathways [ 46 , 64 ], including the regulation of autophagy [ 65 ], kinases, and pro-apoptotic proteins such as caspases [ 66 , 67 , 68 ].…”

“…Earlier studies have effectively described the vital role of oxidative stress by H 2 O 2 in inhibiting cell proliferation in various cells [62], including RPE in the retina [35,46,63,64]. The exact mechanisms have not been identified, however, recent studies have revealed the interference of H 2 O 2 in numerous intracellular signaling pathways in retinal epithelial cells, such as the epidermal growth factor receptor/AKT and Notch signaling pathways [46,64], including the regulation of autophagy [65], kinases, and proapoptotic proteins such as caspases [66][67][68]. These studies open the way towards future identification of the mechanisms involved in the interplay between vitamin D and retinal cells in restoring cell proliferation and protecting RPE from angiogenesis.…”

COVID-19 and retinal degenerative diseases: Promising link “Kaempferol”

“…On the other hand, hyperoxic insult and apoptosis have been examined in the presence of various vitamins as a rescuing factor [ 100 ]. Kaempferol protects retinal pigment epithelium cells from hydrogen peroxide-induced inflammation and apoptosis by activating SIRT1 and inhibiting PARP1, which opens up a significant gateway for more experiments and further insights [ 101 ].…”

Dietary vitamins, carotenoids and their sources in relation to age-related macular degeneration risk in China: a population-based case–control study

“…3,4 Accordingly, as they are important nonenzymatic anti-oxidative agents in the retina, vitamins and carotenoids were hypothesized to protect the retina from oxidative damage, which suggests that these nutrients play an important role in preventing the process of vision impairment. 5,6 In particular, lutein and its structural isomer, zeaxanthin, which are concentrated in the macula, have also been suggested to play a role in protecting the macular region by acting as a blue light filter, thereby decreasing photochemical light damage. 7 To date, conflicting results have been reported on the association between the intakes of antioxidants, such as lutein, vitamin C and β-carotene, and AMD, with some demonstrating a possible inverse association have been reported [8][9][10][11][12][13] , whereas other studies showed no clear association.…”