Oxidative Stress-Induced Pentraxin 3 Expression Human Retinal Pigment Epithelial Cells is Involved in the Pathogenesis of Age-Related Macular Degeneration.

Hwang Hwang,Chung Chung,Woo Woo,Kwon Kwon

doi:10.3390/ijms20236028

Abstract

(1) Background: Age-related macular degeneration (AMD) is closely related with retinal pigment epithelial (RPE) cell dysfunction. Although the exact pathogenesis of AMD remains largely unknown, oxidative stress-induced RPE damage is believed to be one of the primary causes. We investigated the molecular mechanisms of pentraxin 3 (PTX3) expression and its biological functions during oxidative injury. (2) Methods: Using enzyme-linked immunosorbent assays and real-time reverse transcription-polymerase chain reaction, we analyzed mRNA and protein levels of PTX3 in the presence or absence of oxidative stress inducer, sodium iodate (NaIO3), in primary human H-RPE and ARPE-19 cells. Furthermore, we assessed cell death, antioxidant enzyme expression, and AMD-associated gene expression to determine the biological functions of PTX3 under oxidative stress. (3) Results: NaIO3 increased PTX3 expression, in a dose- and time-dependent manner, in H-RPE and ARPE-19 cells. We found phosphorylated Akt, a downstream target of the PI3 kinase pathway, phosphor- mitogen-activated protein kinase kinase 1/2 (ERK), and intracellular reactive oxygen species (ROS) were predominantly induced by NaIO3. NaIO3-induced PTX3 expression was decreased in the presence of phosphoinositide 3 (PI3) kinase inhibitors, ERK inhibitors, and ROS scavengers. Furthermore, NaIO3 enhanced mRNA expression of antioxidant enzymes such as glucose-6-phosphate dehydrogenase (G6PDH), catalase (CAT), and glutathione S-reductase (GSR) in the control shRNA expressing RPE cells, but not in hPTX3 shRNA expressing RPE cells. Interestingly, NaIO3 did not induce mRNA expression of AMD marker genes, such as complement factor I (CFI), complement factor H (CFH), apolipoprotein E (APOE), and toll-like receptor 4 (TLR4) in hPTX3 shRNA expressing RPE cells. 4) Conclusions: These results suggest that PTX3 accelerates RPE cell death and might be involved in AMD development in the presence of oxidative stress.

Highlights

The retinal pigment epithelium (RPE), a monolayer located between the photoreceptors and the choroid, is essential for survival of the retina, including maintaining the overlying photoreceptors, mediating the uptake of nutrients, ions, and water, and phagocytizing the shed photoreceptor outer segment [1]
4) Conclusions: These results suggest that pentraxin 3 (PTX3) accelerates RPE cell death and might be involved in age-related macular degeneration (AMD) development in the presence of oxidative stress
Described observations suggest that PTX3 expression was enhanced in response to either pro-inflammatory mediators or endoplasmic reticulum stress inducers in human RPE cells

Summary

Introduction

The retinal pigment epithelium (RPE), a monolayer located between the photoreceptors and the choroid, is essential for survival of the retina, including maintaining the overlying photoreceptors, mediating the uptake of nutrients, ions, and water, and phagocytizing the shed photoreceptor outer segment [1]. Several retinal degenerative diseases, including age-related macular degeneration (AMD), are closely related with RPE dysfunction [2]. Due to intense illumination from focal light, high oxygen tension in the macular area, and phagocytosis of photoreceptor outer segments, RPE cells are sensitive to oxidative stress [3]. The exact pathogenesis of AMD remains largely unknown, oxidative stress-induced RPE damage is believed to be one of the primary causes [4,5]. Cellular oxidative stress plays an important role in RPE cell death during aging and the development of AMD, the primary cause of blindness in elderly persons [6].

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