Attenuation of High Glucose-Induced Damage in RPE Cells Through P38 MAPK Signaling Pathway Inhibition

Overview

Journal Front Pharmacol

Date 2021 May 24

PMID 34025440

Citations 18

Authors

Grazia Maugeri

Claudio Bucolo

Filippo Drago

Settimio Rossi

Michelino Di Rosa

Rosa Imbesi

Velia DAgata

Salvatore Giunta

Affiliations

Soon will be listed here.

Abstract

This study aimed to investigate the high glucose damage on human retinal pigment epithelial (RPE) cells, the role of p38 MAPK signaling pathway and how dimethyl fumarate can regulate that. We carried out studies on ARPE-19 cells exposed to physiological and high glucose (HG) conditions, to evaluate the effects of DMF on cell viability, apoptosis, and expression of inflammatory and angiogenic biomarkers such as COX-2, iNOS, IL-1β, and VEGF. Our data have demonstrated that DMF treatment attenuated HG-induced apoptosis, as confirmed by reduction of BAX/Bcl-2 ratio. Furthermore, in RPE cells exposed to HG we observed a significant increase of iNOS, COX-2, and IL-1β expression, that was reverted by DMF treatment. Moreover, DMF reduced the VEGF levels elicited by HG, inhibiting p38 MAPK signaling pathway. The present study demonstrated that DMF provides a remarkable protection against high glucose-induced damage in RPE cells through p38 MAPK inhibition and the subsequent down-regulation of VEGF levels, suggesting that DMF is a small molecule that represents a good candidate for diabetic retinopathy treatment and warrants further and clinical evaluation.

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References

Kern T . Contributions of inflammatory processes to the development of the early stages of diabetic retinopathy. Exp Diabetes Res. 2008; 2007:95103. PMC: 2216058. DOI: 10.1155/2007/95103. View

Boss J, Singh P, Pandya H, Tosi J, Kim C, Tewari A . Assessment of Neurotrophins and Inflammatory Mediators in Vitreous of Patients With Diabetic Retinopathy. Invest Ophthalmol Vis Sci. 2017; 58(12):5594-5603. PMC: 5667399. DOI: 10.1167/iovs.17-21973. View

Joussen A, Poulaki V, Le M, Koizumi K, Esser C, Janicki H . A central role for inflammation in the pathogenesis of diabetic retinopathy. FASEB J. 2004; 18(12):1450-2. DOI: 10.1096/fj.03-1476fje. View

Shin E, Huang Q, Gurel Z, Sorenson C, Sheibani N . High glucose alters retinal astrocytes phenotype through increased production of inflammatory cytokines and oxidative stress. PLoS One. 2014; 9(7):e103148. PMC: 4113377. DOI: 10.1371/journal.pone.0103148. View

Foresti R, Bucolo C, Platania C, Drago F, Dubois-Rande J, Motterlini R . Nrf2 activators modulate oxidative stress responses and bioenergetic profiles of human retinal epithelial cells cultured in normal or high glucose conditions. Pharmacol Res. 2015; 99:296-307. DOI: 10.1016/j.phrs.2015.07.006. View

Schlingemann R . Role of growth factors and the wound healing response in age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol. 2003; 242(1):91-101. DOI: 10.1007/s00417-003-0828-0. View

Kim D, Park M, Choi J, Lim S, Choi H, Park S . Hyperglycemia-induced GLP-1R downregulation causes RPE cell apoptosis. Int J Biochem Cell Biol. 2014; 59:41-51. DOI: 10.1016/j.biocel.2014.11.018. View

Campochiaro P . Ocular neovascularization. J Mol Med (Berl). 2013; 91(3):311-21. PMC: 3584193. DOI: 10.1007/s00109-013-0993-5. View

DAmico A, Maugeri G, Rasa D, La Cognata V, Saccone S, Federico C . NAP counteracts hyperglycemia/hypoxia induced retinal pigment epithelial barrier breakdown through modulation of HIFs and VEGF expression. J Cell Physiol. 2017; 233(2):1120-1128. DOI: 10.1002/jcp.25971. View

10.

Yancopoulos G, Davis S, Gale N, Rudge J, Wiegand S, Holash J . Vascular-specific growth factors and blood vessel formation. Nature. 2000; 407(6801):242-8. DOI: 10.1038/35025215. View

11.

Xiao J, Yao J, Jia L, Lin C, Zacks D . Protective Effect of Met12, a Small Peptide Inhibitor of Fas, on the Retinal Pigment Epithelium and Photoreceptor After Sodium Iodate Injury. Invest Ophthalmol Vis Sci. 2017; 58(3):1801-1810. PMC: 5374881. DOI: 10.1167/iovs.16-21392. View

12.

Nishioku T, Kawamoto M, Okizono R, Sakai E, Okamoto K, Tsukuba T . Dimethyl fumarate prevents osteoclastogenesis by decreasing NFATc1 expression, inhibiting of erk and p38 MAPK phosphorylation, and suppressing of HMGB1 release. Biochem Biophys Res Commun. 2020; 530(2):455-461. DOI: 10.1016/j.bbrc.2020.05.088. View

13.

Xia T, Rizzolo L . Effects of diabetic retinopathy on the barrier functions of the retinal pigment epithelium. Vision Res. 2017; 139:72-81. DOI: 10.1016/j.visres.2017.02.006. View

14.

Du Y, Veenstra A, Palczewski K, Kern T . Photoreceptor cells are major contributors to diabetes-induced oxidative stress and local inflammation in the retina. Proc Natl Acad Sci U S A. 2013; 110(41):16586-91. PMC: 3799310. DOI: 10.1073/pnas.1314575110. View

15.

Bucolo C, Gozzo L, Longo L, Mansueto S, Vitale D, Drago F . Long-term efficacy and safety profile of multiple injections of intravitreal dexamethasone implant to manage diabetic macular edema: A systematic review of real-world studies. J Pharmacol Sci. 2018; 138(4):219-232. DOI: 10.1016/j.jphs.2018.11.001. View

16.

Bucolo C, Drago F, Maisto R, Romano G, DAgata V, Maugeri G . Curcumin prevents high glucose damage in retinal pigment epithelial cells through ERK1/2-mediated activation of the Nrf2/HO-1 pathway. J Cell Physiol. 2019; 234(10):17295-17304. DOI: 10.1002/jcp.28347. View

17.

Zhao G, Liu Y, Fang J, Chen Y, Li H, Gao K . Dimethyl fumarate inhibits the expression and function of hypoxia-inducible factor-1α (HIF-1α). Biochem Biophys Res Commun. 2014; 448(3):303-7. DOI: 10.1016/j.bbrc.2014.02.062. View

18.

Sone H, Kawakami Y, Okuda Y, Kondo S, Hanatani M, Suzuki H . Vascular endothelial growth factor is induced by long-term high glucose concentration and up-regulated by acute glucose deprivation in cultured bovine retinal pigmented epithelial cells. Biochem Biophys Res Commun. 1996; 221(1):193-8. DOI: 10.1006/bbrc.1996.0568. View

19.

Platania C, Giurdanella G, di Paola L, Leggio G, Drago F, Salomone S . P2X7 receptor antagonism: Implications in diabetic retinopathy. Biochem Pharmacol. 2017; 138:130-139. DOI: 10.1016/j.bcp.2017.05.001. View

20.

Grant M, Afzal A, Spoerri P, Pan H, Shaw L, Mames R . The role of growth factors in the pathogenesis of diabetic retinopathy. Expert Opin Investig Drugs. 2004; 13(10):1275-93. DOI: 10.1517/13543784.13.10.1275. View