Abstract
PurposeAll-trans retinoic acid (ATRA) plays an important role in ocular development. Previous studies found that retinoic acid could influence the metabolism of scleral remodeling by promoting retinal pigment epithelium (RPE) cells to secrete secondary signaling factors. The purpose of this study was to investigate whether retinoic acid affected secretion of bone morphogenetic protein 2 (BMP-2) and matrix metalloproteinase 2 (MMP-2) and to explore the signaling pathway of retinoic acid in cultured acute retinal pigment epithelial 19 (ARPE-19) cells.MethodsThe effects of ATRA (concentrations from 10−9 to 10−5 mol/l) on the expression of retinoic acid receptors (RARs) in ARPE-19 cells were examined at the mRNA and protein levels using reverse transcription-polymerase chain reaction (RT-PCR) and western blot assay, respectively. The effects of treating ARPE-19 cells with ATRA concentrations ranging from 10−9 to 10−5 mol/l for 24 h and 48 h or with 10-6mol/l ATRA at different times ranging from 6h to 72h were assessed using real-time quantitative PCR (qPCR) and enzyme-linked immunosorbent assay (ELISA). The contribution of RARβ-induced activation of ARPE-19 cells was confirmed using LE135, an antagonist of RARβ.ResultsRARβ mRNA levels significantly increased in the ARPE-19 cells treated with ATRA for 24h and 48h. These increases in RARβ mRNA levels were dose dependent (at concentrations of 10−9 to 10−5 mol/l) with a maximum effect observed at 10−6 mol/l. There were no significant changes in the mRNA levels of RARα and RARγ. Western blot assay revealed that RARβ protein levels were increased significantly in a time-dependent manner in ARPE-19 cells treated with 10−6 mol/l ATRA from 12 h to 72 h, with a marked increase observed at 24 h and 48 h. The upregulation of RARβ and the ATRA-induced secretion in ARPE-19 cells could be inhibited by the RARβ antagonist LE135.ConclusionATRA induced upregulation of RARβ in ARPE-19 cells and stimulated these cells to secrete BMP-2 and MMP-2.
Highlights
Myopia has become a major public health problem worldwide, with a prevalence ranging from 20–30% in North American and European populations to 80–90% in East Asian populations [1,2,3,4]
RARβ mRNA levels significantly increased in the acute retinal pigment epithelial 19 (ARPE-19) cells treated with All-trans retinoic acid (ATRA) for 24h and 48h
These increases in RARβ mRNA levels were dose dependent with a maximum effect observed at 10−6 mol/l
Summary
Myopia has become a major public health problem worldwide, with a prevalence ranging from 20–30% in North American and European populations to 80–90% in East Asian populations [1,2,3,4]. RA is a metabolic product of retinol, the active from of vitamin A, and interacts with two distinct types of intracellular proteins. RA interacts with cellular retinoicacid-binding proteins (CRABPs), which are primarily involved in the storage, intracellular transport and metabolism of RA [8]. RA interacts mainly with two families of nuclear retinoid receptor proteins: retinoic acid receptors (RARs) and retinoid “X” receptors (RXRs). Both RARs and RXRs have α, β and γ subtypes with different expression patterns in different cells and tissues [9]. RA exerts its biological functions primarily by binding to and activating specific nuclear receptors [10, 11]
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