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. 2023 Jun 18;16(6):849-854.
doi: 10.18240/ijo.2023.06.03. eCollection 2023.

All-trans retinoic acid regulates the expression of MMP-2 and TGF-β2 via RDH5 in retinal pigment epithelium cells

Yu-Mei Mao  1   2 , Chang-Jun Lan  1   2 , Qing-Qing Tan  1   2 , Gui-Mei Zhou  1   2 , Xiao-Ling Xiang  1   2 , Jia Lin  1   2 , Xuan Liao  1   2
Affiliations

All-trans retinoic acid regulates the expression of MMP-2 and TGF-β2 via RDH5 in retinal pigment epithelium cells

Yu-Mei Mao et al. Int J Ophthalmol. .

Abstract

Aim: To investigate the effect of all-trans retinoic acid (ATRA) on retinol dehydrogenase 5 (RDH5), matrix metalloproteinase-2 (MMP-2) and transforming growth factor-β2 (TGF-β2) transcription levels, and the effect of RDH5 on MMP-2 and TGF-β2 in retinal pigment epithelium (RPE) cells.

Methods: After adult RPE cell line-19 (ARPE-19 cells) intervened with gradient concentrations of ATRA (0-20 µmol/L) for 24h, flow cytometry was used to detect the proliferation and apoptosis of cells in each group, and quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect RDH5, MMP-2 and TGF-β2 mRNA expression. Then, after ARPE-19 cells transfected with three different siRNA targets for 48h, the RDH5 knockdown efficiency of each group and expression of MMP-2 and TGF-β2 mRNA within them was detected by qRT-PCR.

Results: Flow cytometry results showed that ATRA could inhibit the proliferation of RPE cells and promote the apoptosis of RPE cells, and the difference of apoptosis was statistically significant when the ATRA concentration exceeded 5 µmol/L and compared with the normal control group (P=0.027 and P=0.031, respectively). qRT-PCR results showed that ATRA could significantly inhibit the expression level of RDH5 mRNA (P<0.001) and promote the expression of MMP-2 and TGF-β2 mRNA (P=0.03 and P<0.001, respectively) in a dose-dependent manner, especially when treated with 5 µmol/L ATRA. The knockdown efficiency of RDH5 siRNA varies with different targets, among which RDH5 siRNA-435 had the highest knockdown efficiency, i.e., more than 50% lower than that of the negative control group (P=0.02). When RDH5 was knocked down for 48h, the results of qRT-PCR showed that the expressions of MMP-2 and TGF-β2 mRNA were significantly up-regulated (P<0.001).

Conclusion: ATRA inhibits the expression of RDH5 and promotes MMP-2 and TGF-β2, and further RDH5 knockdown significantly upregulates MMP-2 and TGF-β2. These findings suggest that RDH5 may be involved in an epithelial-mesenchymal transition of RPE cells mediated by ATRA.

Keywords: ARPE-19; all-trans retinoic acid; matrix metalloproteinase-2; retinol dehydrogenase 5; transforming growth factor-β2.

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Figures

Figure 1
Figure 1. Changes of apoptosis level of ARPE-19 cells induced by ATRA
The upper right quadrant was the early apoptotic cell population, and the lower right quadrant was the late apoptotic cell population. ATRA: All-trans retinoic acid; ARPE: Adult retinal pigment epithelium.
Figure 2
Figure 2. Quantitative analysis of the effects of different concentrations of ATRA on the mRNA expressions of RDH5, MMP-2, and TGF-β2
Compared with the control group, aP<0.05, bP<0.01, cP<0.001. ATRA: All-trans retinoic acid; ARPE: Adult retinal pigment epithelium; RDH: Retinol dehydrogenase; MMP: Matrix metalloproteinase; TGF: Transforming growth factor.
Figure 3
Figure 3. The effect of RDH5 siRNA with different targets on the knockdown efficiency of RDH5 gene
Compared with the negative control, aP<0.05, dP<0.001. RDH: Retinol dehydrogenase.
Figure 4
Figure 4. The effect of target RDH5 siRNA-435 on MMP-2 and TGF-β2 mRNA expression
Compared with the negative control, dP<0.001. RDH: Retinol dehydrogenase; MMP: Matrix metalloproteinase; TGF: Transforming growth factor.
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