Skip to main content
Top
Published in: BMC Ophthalmology 1/2019

Open Access 01-12-2019 | Research article

All-trans retinoic acid stimulates the secretion of TGF-β2 via the phospholipase C but not the adenylyl cyclase signaling pathway in retinal pigment epithelium cells

Authors: Daren Zhang, Zhihong Deng, Jia Tan, Shuirong Liu, Shuyu Hu, Hui Tao, Renhong Tang

Published in: BMC Ophthalmology | Issue 1/2019

Login to get access

Abstract

Background

By investigating that (i) all-trans retinoic acid (ATRA) affects human retinal pigment epithelium (RPE) in expressing and secreting transforming growth factor (TGF)-β2 and (ii) U73122 (phospholipase C inhibitor) and SQ22536 (adenylyl cyclase inhibitor) regulate the ATRA-induced secretion of TGF-β2 in human RPE, we sought to interpret the signaling pathway of ATRA in promoting the development of myopia.

Methods

The RPE cell line (D407) was treated with (i) ATRA (10 μM), (ii) U73122 (5–40 μM) and ATRA (10 μM), or (iii) SQ22536 (5–40 μM) and ATRA (10 μM). The control group was no-treated. After stimulated at 2, 4, 8, 16, 24, and 48 h, The expression and secretion of TGF-β2 was detected.

Results

TGF-β2 in the cytoplasm was time-dependent increased by ATRA (p < 0.001). A time-dependent increase in the TGF-β2 protein of the supernatant was induced by ATRA (p < 0.001). U73122 (in the range of 5 to 40 μM) could suppress the secretion of TGF-β2 induced by ATRA (p < 0.001), and 40 μM U73122 could completely inhibit the up-regulated effect of 10 μM ATRA. However, SQ22536 (in the range of 5 to 40 μM) had no impact on the secretion of TGF-β2 induced by ATRA (p > 0.05).

Conclusions

In RPE cells, ATRA stimulates the secretion of TGF-β2 via the phospholipase C signaling pathway but not the adenylyl cyclase signaling pathway. U73122 may inhibit the promotion of ATRA in the development of myopia.
Literature
1.
go back to reference Durston AJ, Timmermans JP, Hage WJ, Hendriks HF, de Vries NJ, Heideveld M, Nieuwkoop PD. Retinoic acid causes an anteroposterior transformation in the developing central nervous system. Nature. 1989;340:140–4.CrossRef Durston AJ, Timmermans JP, Hage WJ, Hendriks HF, de Vries NJ, Heideveld M, Nieuwkoop PD. Retinoic acid causes an anteroposterior transformation in the developing central nervous system. Nature. 1989;340:140–4.CrossRef
2.
go back to reference Osanai M, Petkovich M. Expression of the retinoic acid-metabolizing enzyme CYP26A1 limits programmed cell death. Mol Pharmacol. 2005;67:1808–17.CrossRef Osanai M, Petkovich M. Expression of the retinoic acid-metabolizing enzyme CYP26A1 limits programmed cell death. Mol Pharmacol. 2005;67:1808–17.CrossRef
3.
go back to reference Bitzer M, Feldkaemper M, Schaeffel F. Visually induced changes in components of the retinoic acid system in fundal layers of the chick. Exp Eye Res. 2000;70:97–106.CrossRef Bitzer M, Feldkaemper M, Schaeffel F. Visually induced changes in components of the retinoic acid system in fundal layers of the chick. Exp Eye Res. 2000;70:97–106.CrossRef
4.
go back to reference Huang J, Qu XM, Chu RY. Expressions of cellular retinoic acid binding proteins I and retinoic acid receptor-beta in the Guinea pig eyes with experimental myopia. Int J Ophthalmol. 2011;4:131–6.PubMedPubMedCentral Huang J, Qu XM, Chu RY. Expressions of cellular retinoic acid binding proteins I and retinoic acid receptor-beta in the Guinea pig eyes with experimental myopia. Int J Ophthalmol. 2011;4:131–6.PubMedPubMedCentral
5.
go back to reference McFadden SA, Howlett MH, Mertz JR. Retinoic acid signals the direction of ocular elongation in the Guinea pig eye. Vis Res. 2004;44:643–53.CrossRef McFadden SA, Howlett MH, Mertz JR. Retinoic acid signals the direction of ocular elongation in the Guinea pig eye. Vis Res. 2004;44:643–53.CrossRef
6.
go back to reference McFadden SA, Howlett MH, Mertz JR, Wallman J. Acute effects of dietary retinoic acid on ocular components in the growing chick. Exp Eye Res. 2006;83:949–61.CrossRef McFadden SA, Howlett MH, Mertz JR, Wallman J. Acute effects of dietary retinoic acid on ocular components in the growing chick. Exp Eye Res. 2006;83:949–61.CrossRef
7.
go back to reference Seko Y, Shimizu M, Tokoro T. Retinoic acid increases in the retina of the chick with form deprivation myopia. Ophthalmic Res. 1998;30:361–7.CrossRef Seko Y, Shimizu M, Tokoro T. Retinoic acid increases in the retina of the chick with form deprivation myopia. Ophthalmic Res. 1998;30:361–7.CrossRef
8.
go back to reference Troilo D, Nickla DL, Mertz JR, Summers Rada JA. Change in the synthesis rates of ocular retinoic acid and scleral glycosaminoglycan during experimentally altered eye growth in marmosets. Invest Ophthalmol Vis Sci. 2006;47:1768–77.CrossRef Troilo D, Nickla DL, Mertz JR, Summers Rada JA. Change in the synthesis rates of ocular retinoic acid and scleral glycosaminoglycan during experimentally altered eye growth in marmosets. Invest Ophthalmol Vis Sci. 2006;47:1768–77.CrossRef
9.
go back to reference Mao J, Liu S. Regulation of RPE barrier function by all-trans retinoic acid in myopia. Neurosci Lett. 2014;568:17–22.CrossRef Mao J, Liu S. Regulation of RPE barrier function by all-trans retinoic acid in myopia. Neurosci Lett. 2014;568:17–22.CrossRef
10.
go back to reference Wang S, Liu S, Mao J, Wen D. Effect of retinoic acid on the tight junctions of the retinal pigment epithelium-choroid complex of Guinea pigs with lens-induced myopia in vivo. Int J Mol Med. 2014;33:825–32.CrossRef Wang S, Liu S, Mao J, Wen D. Effect of retinoic acid on the tight junctions of the retinal pigment epithelium-choroid complex of Guinea pigs with lens-induced myopia in vivo. Int J Mol Med. 2014;33:825–32.CrossRef
11.
go back to reference Hollborn M, Enzmann V, Barth W, Wiedemann P, Kohen L. Changes in the mRNA expression of cytokines and chemokines by stimulated RPE cells in vitro. Curr Eye Res. 2000;20:488–95.CrossRef Hollborn M, Enzmann V, Barth W, Wiedemann P, Kohen L. Changes in the mRNA expression of cytokines and chemokines by stimulated RPE cells in vitro. Curr Eye Res. 2000;20:488–95.CrossRef
12.
go back to reference Kociok N, Heppekausen H, Schraermeyer U, Esser P, Thumann G, Grisanti S, Heimann K. The mRNA expression of cytokines and their receptors in cultured iris pigment epithelial cells: a comparison with retinal pigment epithelial cells. Exp Eye Res. 1998;67:237–50.CrossRef Kociok N, Heppekausen H, Schraermeyer U, Esser P, Thumann G, Grisanti S, Heimann K. The mRNA expression of cytokines and their receptors in cultured iris pigment epithelial cells: a comparison with retinal pigment epithelial cells. Exp Eye Res. 1998;67:237–50.CrossRef
13.
go back to reference Rosenthal R, Malek G, Salomon N, Peill-Meininghaus M, Coeppicus L, Wohlleben H, Wimmers S, Bowes RC, Strauss O. The fibroblast growth factor receptors, FGFR-1 and FGFR-2, mediate two independent signalling pathways in human retinal pigment epithelial cells. Biochem Biophys Res Commun. 2005;337:241–7.CrossRef Rosenthal R, Malek G, Salomon N, Peill-Meininghaus M, Coeppicus L, Wohlleben H, Wimmers S, Bowes RC, Strauss O. The fibroblast growth factor receptors, FGFR-1 and FGFR-2, mediate two independent signalling pathways in human retinal pigment epithelial cells. Biochem Biophys Res Commun. 2005;337:241–7.CrossRef
14.
go back to reference Nagineni CN, Cherukuri KS, Kutty V, Detrick B, Hooks JJ. Interferon-gamma differentially regulates TGF-beta1 and TGF-beta2 expression in human retinal pigment epithelial cells through JAK-STAT pathway. J Cell Physiol. 2007;210:192–200.CrossRef Nagineni CN, Cherukuri KS, Kutty V, Detrick B, Hooks JJ. Interferon-gamma differentially regulates TGF-beta1 and TGF-beta2 expression in human retinal pigment epithelial cells through JAK-STAT pathway. J Cell Physiol. 2007;210:192–200.CrossRef
15.
go back to reference Jia Y, Hu DN, Zhou J. Human aqueous humor levels of TGF- beta2: relationship with axial length. Biomed Res Int. 2014;2014:258591.PubMedPubMedCentral Jia Y, Hu DN, Zhou J. Human aqueous humor levels of TGF- beta2: relationship with axial length. Biomed Res Int. 2014;2014:258591.PubMedPubMedCentral
16.
go back to reference Chen BY, Wang CY, Chen WY, Ma JX. Altered TGF-beta2 and bFGF expression in scleral desmocytes from an experimentally-induced myopia Guinea pig model. Graefes Arch Clin Exp Ophthalmol. 2013;251:1133–44.CrossRef Chen BY, Wang CY, Chen WY, Ma JX. Altered TGF-beta2 and bFGF expression in scleral desmocytes from an experimentally-induced myopia Guinea pig model. Graefes Arch Clin Exp Ophthalmol. 2013;251:1133–44.CrossRef
17.
go back to reference Lin HJ, Wan L, Tsai Y, Liu SC, Chen WC, Tsai SW, Tsai FJ. Sclera-related gene polymorphisms in high myopia. Mol Vis. 2009;15:1655–63.PubMedPubMedCentral Lin HJ, Wan L, Tsai Y, Liu SC, Chen WC, Tsai SW, Tsai FJ. Sclera-related gene polymorphisms in high myopia. Mol Vis. 2009;15:1655–63.PubMedPubMedCentral
18.
go back to reference Jobling AI, Wan R, Gentle A, Bui BV, McBrien NA. Retinal and choroidal TGF-beta in the tree shrew model of myopia: isoform expression, activation and effects on function. Exp Eye Res. 2009;88:458–66.CrossRef Jobling AI, Wan R, Gentle A, Bui BV, McBrien NA. Retinal and choroidal TGF-beta in the tree shrew model of myopia: isoform expression, activation and effects on function. Exp Eye Res. 2009;88:458–66.CrossRef
19.
go back to reference Jobling AI, Gentle A, Metlapally R, McGowan BJ, McBrien NA. Regulation of scleral cell contraction by transforming growth factor-beta and stress: competing roles in myopic eye growth. J Biol Chem. 2009;284:2072–9.CrossRef Jobling AI, Gentle A, Metlapally R, McGowan BJ, McBrien NA. Regulation of scleral cell contraction by transforming growth factor-beta and stress: competing roles in myopic eye growth. J Biol Chem. 2009;284:2072–9.CrossRef
20.
go back to reference Jobling AI, Nguyen M, Gentle A, McBrien NA. Isoform-specific changes in scleral transforming growth factor-beta expression and the regulation of collagen synthesis during myopia progression. J Biol Chem. 2004;279:18121–6.CrossRef Jobling AI, Nguyen M, Gentle A, McBrien NA. Isoform-specific changes in scleral transforming growth factor-beta expression and the regulation of collagen synthesis during myopia progression. J Biol Chem. 2004;279:18121–6.CrossRef
21.
go back to reference Tan J, Deng ZH, Liu SZ, Wang JT, Huang C. TGF-beta(2) in human retinal pigment epithelial cells: expression and secretion regulated by cholinergic signals in vitro. Curr Eye Res. 2010;35(1):37–44.CrossRef Tan J, Deng ZH, Liu SZ, Wang JT, Huang C. TGF-beta(2) in human retinal pigment epithelial cells: expression and secretion regulated by cholinergic signals in vitro. Curr Eye Res. 2010;35(1):37–44.CrossRef
22.
go back to reference Campochiaro PA, Hackett SF, Conway BP. Retinoic acid promotes density-dependent growth arrest in human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci. 1991;32:65–72.PubMed Campochiaro PA, Hackett SF, Conway BP. Retinoic acid promotes density-dependent growth arrest in human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci. 1991;32:65–72.PubMed
23.
go back to reference Uchida H, Hayashi H, Kuroki M, Uno K, Yamada H, Yamashita Y, Tombran-Tink J, Kuroki M, Oshima K. Vitamin a up-regulates the expression of thrombospondin-1 and pigment epithelium-derived factor in retinal pigment epithelial cells. Exp Eye Res. 2005;80:23–30.CrossRef Uchida H, Hayashi H, Kuroki M, Uno K, Yamada H, Yamashita Y, Tombran-Tink J, Kuroki M, Oshima K. Vitamin a up-regulates the expression of thrombospondin-1 and pigment epithelium-derived factor in retinal pigment epithelial cells. Exp Eye Res. 2005;80:23–30.CrossRef
24.
go back to reference Uchida H, Kuroki M, Shitama T, Hayashi H, Kuroki M. Activation of TGF-beta1 through up-regulation of TSP-1 by retinoic acid in retinal pigment epithelial cells. Curr Eye Res. 2008;33:199–203.CrossRef Uchida H, Kuroki M, Shitama T, Hayashi H, Kuroki M. Activation of TGF-beta1 through up-regulation of TSP-1 by retinoic acid in retinal pigment epithelial cells. Curr Eye Res. 2008;33:199–203.CrossRef
25.
go back to reference Mao JF, Liu SZ. Mechanism of the DL-alpha-aminoadipic acid inhibitory effect on form-deprived myopia in Guinea pig. Int J Ophthalmol. 2013;6:19–22.PubMedPubMedCentral Mao JF, Liu SZ. Mechanism of the DL-alpha-aminoadipic acid inhibitory effect on form-deprived myopia in Guinea pig. Int J Ophthalmol. 2013;6:19–22.PubMedPubMedCentral
26.
go back to reference Wu PC, Tsai CL, Gordon GM, Jeong S, Itakura T, Patel N, Shi S, Fini ME. Chondrogenesis in scleral stem/progenitor cells and its association with form-deprived myopia in mice. Mol Vis. 2015;21:138–47.PubMedPubMedCentral Wu PC, Tsai CL, Gordon GM, Jeong S, Itakura T, Patel N, Shi S, Fini ME. Chondrogenesis in scleral stem/progenitor cells and its association with form-deprived myopia in mice. Mol Vis. 2015;21:138–47.PubMedPubMedCentral
27.
go back to reference Das BC, Thapa P, Karki R, Das S, Mahapatra S, Liu TC, Torregroza I, Wallace DP, Kambhampati S, Van VP, Verma A, Ray SK. Evans T (2014) retinoic acid signaling pathways in development and diseases. Bioorg Med Chem. 2014;22:673–83.CrossRef Das BC, Thapa P, Karki R, Das S, Mahapatra S, Liu TC, Torregroza I, Wallace DP, Kambhampati S, Van VP, Verma A, Ray SK. Evans T (2014) retinoic acid signaling pathways in development and diseases. Bioorg Med Chem. 2014;22:673–83.CrossRef
28.
go back to reference Thoreson WB, Ryan JS, Shi C, Kelly ME, Bryson EJ, Toews ML, Ediger TL, Chacko DM. Lysophosphatidic acid receptor signaling in mammalian retinal pigment epithelial cells. Invest Ophthalmol Vis Sci. 2002;43:2450–61.PubMed Thoreson WB, Ryan JS, Shi C, Kelly ME, Bryson EJ, Toews ML, Ediger TL, Chacko DM. Lysophosphatidic acid receptor signaling in mammalian retinal pigment epithelial cells. Invest Ophthalmol Vis Sci. 2002;43:2450–61.PubMed
Metadata
Title
All-trans retinoic acid stimulates the secretion of TGF-β2 via the phospholipase C but not the adenylyl cyclase signaling pathway in retinal pigment epithelium cells
Authors
Daren Zhang
Zhihong Deng
Jia Tan
Shuirong Liu
Shuyu Hu
Hui Tao
Renhong Tang
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Ophthalmology / Issue 1/2019
Electronic ISSN: 1471-2415
DOI
https://doi.org/10.1186/s12886-018-1017-6

Other articles of this Issue 1/2019

BMC Ophthalmology 1/2019 Go to the issue