Skip to main content
Top
Published in: BMC Ophthalmology 1/2017

Open Access 01-12-2017 | Research article

Cyclic stretch induced-retinal pigment epithelial cell apoptosis and cytokine changes

Authors: Shen Wu, Qingjun Lu, Ningli Wang, Jingxue Zhang, Qian Liu, Meng Gao, Jinqiu Chen, Wu Liu, Liang Xu

Published in: BMC Ophthalmology | Issue 1/2017

Login to get access

Abstract

Background

The pathogenesis of age-related macular degeneration (AMD) is complex. It has been shown that vitreomacular traction (VMT) plays a role in the pathogenesis of AMD. We speculate that the continuous stretch induced by VMT might impair the function of retinal pigment epithelium (RPE) cells and it might also be involved in the progression of AMD.

Methods

Cultured ARPE-19 cells were subjected to cyclic stretch on the Flexcell Strain system at a level of 25% increment on the surface area for 8 h, 14 h, 20 h, 24 h. In another group, the stretch was withdrawn at 14 h and the cell cultured for another 6 h. Then, we observed the changes in morphology, apoptosis and expression of interleukin 6 (IL6) and vascular endothelial growth factor (VEGF) in RPE cells under stretch.

Results

We found that stretch induced the RPE cells to change from a spreading shape into a rounded shape, and that the morphological changes were positively correlated with the duration of the stretch. The expression of pFAK397 and pRac1/cdc42 were elevated in a time-dependent fashion. The stretch resulted in an increase in the apoptosis ratio, with Bcl2, Bax and p53 also showing time-dependent changes. In addition, up-regulation of IL6 and VEGF expression levels was also observed. After withdrawal of the stretch, all of these changes were significantly diminished.

Conclusion

Stretch may induce morphological, cell apoptosis, and up-regulation of cytokines changes in RPE cells, indicating that cyclic stretching may participate in the progression of AMD by impeding the functions of the RPE.
Literature
1.
go back to reference Wang H, Hartnett ME. Regulation of signaling events involved in the pathophysiology of neovascular AMD. Mol Vis. 2016;22:189–202.PubMedPubMedCentral Wang H, Hartnett ME. Regulation of signaling events involved in the pathophysiology of neovascular AMD. Mol Vis. 2016;22:189–202.PubMedPubMedCentral
2.
go back to reference Feher J, Kovacs I, Artico M, Cavallotti C, Papale A, Balacco Gabrieli C. Mitochondrial alterations of retinal pigment epithelium in age-related macular degeneration. Neurobiol Aging. 2006;27(7):983–93.CrossRefPubMed Feher J, Kovacs I, Artico M, Cavallotti C, Papale A, Balacco Gabrieli C. Mitochondrial alterations of retinal pigment epithelium in age-related macular degeneration. Neurobiol Aging. 2006;27(7):983–93.CrossRefPubMed
3.
go back to reference Roybal CN, Hunsaker LA, Barbash O, Vander Jagt DL, Abcouwer SF. The oxidative stressor arsenite activates vascular endothelial growth factor mRNA transcription by an ATF4-dependent mechanism. J Biol Chem. 2005;280(21):20331–9.CrossRefPubMed Roybal CN, Hunsaker LA, Barbash O, Vander Jagt DL, Abcouwer SF. The oxidative stressor arsenite activates vascular endothelial growth factor mRNA transcription by an ATF4-dependent mechanism. J Biol Chem. 2005;280(21):20331–9.CrossRefPubMed
4.
go back to reference Anderson DH, Mullins RF, Hageman GS, Johnson LV. A role for local inflammation in the formation of drusen in the aging eye. Am J Ophthalmol. 2002;134(3):411–31.CrossRefPubMed Anderson DH, Mullins RF, Hageman GS, Johnson LV. A role for local inflammation in the formation of drusen in the aging eye. Am J Ophthalmol. 2002;134(3):411–31.CrossRefPubMed
5.
go back to reference Karunadharma PP, Nordgaard CL, Olsen TW, Ferrington DA. Mitochondrial DNA damage as a potential mechanism for age-related macular degeneration. Invest Ophthalmol Vis Sci. 2010;51(11):5470–9.CrossRefPubMedPubMedCentral Karunadharma PP, Nordgaard CL, Olsen TW, Ferrington DA. Mitochondrial DNA damage as a potential mechanism for age-related macular degeneration. Invest Ophthalmol Vis Sci. 2010;51(11):5470–9.CrossRefPubMedPubMedCentral
6.
go back to reference Patel N, Adewoyin T, Chong NV. Age-related macular degeneration: a perspective on genetic studies. Eye. 2008;22(6):768–76.CrossRefPubMed Patel N, Adewoyin T, Chong NV. Age-related macular degeneration: a perspective on genetic studies. Eye. 2008;22(6):768–76.CrossRefPubMed
7.
go back to reference Krebs I, Brannath W, Glittenberg C, Zeiler F, Sebag J, Binder S. Posterior vitreomacular adhesion: a potential risk factor for exudative age-related macular degeneration? Am J Ophthalmol. 2007;144(5):741–6.CrossRefPubMed Krebs I, Brannath W, Glittenberg C, Zeiler F, Sebag J, Binder S. Posterior vitreomacular adhesion: a potential risk factor for exudative age-related macular degeneration? Am J Ophthalmol. 2007;144(5):741–6.CrossRefPubMed
8.
go back to reference Abdillahi H, Enzmann V, Wittwer VV, Wolf S, Wolf-Schnurrbusch UE. Vitreoretinal interface changes in geographic atrophy. Ophthalmology. 2014;121(9):1734–9.CrossRefPubMed Abdillahi H, Enzmann V, Wittwer VV, Wolf S, Wolf-Schnurrbusch UE. Vitreoretinal interface changes in geographic atrophy. Ophthalmology. 2014;121(9):1734–9.CrossRefPubMed
9.
go back to reference Stefanini FR, Maia M, Falabella P, Pfister M, Niemeyer M, Kashani AH, Humayun MS, Koss MJ. Profile of ocriplasmin and its potential in the treatment of vitreomacular adhesion. Clin Ophthalmol. 2014;8:847–56.PubMedPubMedCentral Stefanini FR, Maia M, Falabella P, Pfister M, Niemeyer M, Kashani AH, Humayun MS, Koss MJ. Profile of ocriplasmin and its potential in the treatment of vitreomacular adhesion. Clin Ophthalmol. 2014;8:847–56.PubMedPubMedCentral
10.
go back to reference Waldstein SM, Ritter M, Simader C, Mayr-Sponer U, Kundi M, Schmidt-Erfurth U. Impact of vitreomacular adhesion on ranibizumab mono- and combination therapy for neovascular age-related macular degeneration. Am J Ophthalmol. 2014;158(2):328–36. e321CrossRefPubMed Waldstein SM, Ritter M, Simader C, Mayr-Sponer U, Kundi M, Schmidt-Erfurth U. Impact of vitreomacular adhesion on ranibizumab mono- and combination therapy for neovascular age-related macular degeneration. Am J Ophthalmol. 2014;158(2):328–36. e321CrossRefPubMed
11.
go back to reference Robison CD, Krebs I, Binder S, Barbazetto IA, Kotsolis AI, Yannuzzi LA, Sadun AA, Sebag J. Vitreomacular adhesion in active and end-stage age-related macular degeneration. Am J Ophthalmol. 2009;148(1):79–82. e72CrossRefPubMed Robison CD, Krebs I, Binder S, Barbazetto IA, Kotsolis AI, Yannuzzi LA, Sadun AA, Sebag J. Vitreomacular adhesion in active and end-stage age-related macular degeneration. Am J Ophthalmol. 2009;148(1):79–82. e72CrossRefPubMed
12.
go back to reference Lee SJ, Koh HJ. Effects of vitreomacular adhesion on anti-vascular endothelial growth factor treatment for exudative age-related macular degeneration. Ophthalmology. 2011;118(1):101–10.CrossRefPubMed Lee SJ, Koh HJ. Effects of vitreomacular adhesion on anti-vascular endothelial growth factor treatment for exudative age-related macular degeneration. Ophthalmology. 2011;118(1):101–10.CrossRefPubMed
14.
go back to reference Liu Z, Qin T, Zhou J, Taylor A, Sparrow JR, Shang F. Impairment of the ubiquitin-proteasome pathway in RPE alters the expression of inflammation related genes. Adv Exp Med Biol. 2014;801:237–50.CrossRefPubMedPubMedCentral Liu Z, Qin T, Zhou J, Taylor A, Sparrow JR, Shang F. Impairment of the ubiquitin-proteasome pathway in RPE alters the expression of inflammation related genes. Adv Exp Med Biol. 2014;801:237–50.CrossRefPubMedPubMedCentral
15.
go back to reference Huang C, Wang JJ, Jing G, Li J, Jin C, Yu Q, Falkowski MW, Zhang SX. Erp29 attenuates cigarette smoke extract-induced endoplasmic reticulum stress and mitigates tight junction damage in retinal pigment epithelial cells. Invest Ophthalmol Vis Sci. 2015;56(11):6196–207.CrossRefPubMedPubMedCentral Huang C, Wang JJ, Jing G, Li J, Jin C, Yu Q, Falkowski MW, Zhang SX. Erp29 attenuates cigarette smoke extract-induced endoplasmic reticulum stress and mitigates tight junction damage in retinal pigment epithelial cells. Invest Ophthalmol Vis Sci. 2015;56(11):6196–207.CrossRefPubMedPubMedCentral
16.
go back to reference Chu YK, Lee SC, Byeon SH. VEGF rescues cigarette smoking-induced human RPE cell death by increasing autophagic flux: implications of the role of autophagy in advanced age-related macular degeneration. Invest Ophthalmol Vis Sci. 2013;54(12):7329–37.CrossRefPubMed Chu YK, Lee SC, Byeon SH. VEGF rescues cigarette smoking-induced human RPE cell death by increasing autophagic flux: implications of the role of autophagy in advanced age-related macular degeneration. Invest Ophthalmol Vis Sci. 2013;54(12):7329–37.CrossRefPubMed
17.
go back to reference Montserrat-de la Paz S, Naranjo MC, Bermudez B, Lopez S, Moreda W, Abia R, Muriana FJ. Postprandial dietary fatty acids exert divergent inflammatory responses in retinal-pigmented epithelium cells. Food Funct. 2016;7(3):1345–53.CrossRefPubMed Montserrat-de la Paz S, Naranjo MC, Bermudez B, Lopez S, Moreda W, Abia R, Muriana FJ. Postprandial dietary fatty acids exert divergent inflammatory responses in retinal-pigmented epithelium cells. Food Funct. 2016;7(3):1345–53.CrossRefPubMed
18.
go back to reference Zhang XG, Hui YN, Han QH, Hou X, Huang XF, Ma JX. Cytoskeleton changes of cultured human retinal pigment epithelial cells in a mechanical stress model. Chin J Ophthalmol. 2006;42(2):121–6. Zhang XG, Hui YN, Han QH, Hou X, Huang XF, Ma JX. Cytoskeleton changes of cultured human retinal pigment epithelial cells in a mechanical stress model. Chin J Ophthalmol. 2006;42(2):121–6.
19.
go back to reference Marshall HIW. Primary cilia respond to Uniaxial strain by reorienting and elongating along the Axis of stretch. Biophys J. 2014;106(2):170a. Marshall HIW. Primary cilia respond to Uniaxial strain by reorienting and elongating along the Axis of stretch. Biophys J. 2014;106(2):170a.
20.
go back to reference Sheu SJ, SN W, DN H. Stretch-stimulated activity of large conductance calcium-activated potassium channels in human retinal pigment epithelial cells. J Ocul Pharmacol Ther. 2005;21(6):429–35.CrossRefPubMed Sheu SJ, SN W, DN H. Stretch-stimulated activity of large conductance calcium-activated potassium channels in human retinal pigment epithelial cells. J Ocul Pharmacol Ther. 2005;21(6):429–35.CrossRefPubMed
21.
go back to reference Defilippi P, Olivo C, Venturino M, Dolce L, Silengo L, Tarone G. Actin cytoskeleton organization in response to integrin-mediated adhesion. Microsc Res Tech. 1999;47(1):67–78.CrossRefPubMed Defilippi P, Olivo C, Venturino M, Dolce L, Silengo L, Tarone G. Actin cytoskeleton organization in response to integrin-mediated adhesion. Microsc Res Tech. 1999;47(1):67–78.CrossRefPubMed
22.
go back to reference Bae YH, Mui KL, Hsu BY, Liu SL, Cretu A, Razinia Z, Xu T, Pure E, Assoian RK. A FAK-Cas-Rac-lamellipodin signaling module transduces extracellular matrix stiffness into mechanosensitive cell cycling. Sci Signal. 2014;7(330):ra57.CrossRefPubMedPubMedCentral Bae YH, Mui KL, Hsu BY, Liu SL, Cretu A, Razinia Z, Xu T, Pure E, Assoian RK. A FAK-Cas-Rac-lamellipodin signaling module transduces extracellular matrix stiffness into mechanosensitive cell cycling. Sci Signal. 2014;7(330):ra57.CrossRefPubMedPubMedCentral
23.
go back to reference Huang L, Helmke BP. Polarized actin structural dynamics in response to cyclic uniaxial stretch. Cell Mol Bioeng. 2015;8(1):160–77.CrossRefPubMed Huang L, Helmke BP. Polarized actin structural dynamics in response to cyclic uniaxial stretch. Cell Mol Bioeng. 2015;8(1):160–77.CrossRefPubMed
24.
25.
go back to reference Li W, Sumpio BE. Strain-induced vascular endothelial cell proliferation requires PI3K-dependent mTOR-4E-BP1 signal pathway. Am J Phys Heart Circ Phys. 2005;288(4):H1591–7. Li W, Sumpio BE. Strain-induced vascular endothelial cell proliferation requires PI3K-dependent mTOR-4E-BP1 signal pathway. Am J Phys Heart Circ Phys. 2005;288(4):H1591–7.
26.
go back to reference Wernig F, Mayr M, Xu Q. Mechanical stretch-induced apoptosis in smooth muscle cells is mediated by beta1-integrin signaling pathways. Hypertension. 2003;41(4):903–11.CrossRefPubMed Wernig F, Mayr M, Xu Q. Mechanical stretch-induced apoptosis in smooth muscle cells is mediated by beta1-integrin signaling pathways. Hypertension. 2003;41(4):903–11.CrossRefPubMed
27.
go back to reference Mayr M, Hu Y, Hainaut H, Xu Q. Mechanical stress-induced DNA damage and rac-p38MAPK signal pathways mediate p53-dependent apoptosis in vascular smooth muscle cells. FASEB J. 2002;16(11):1423–5.PubMed Mayr M, Hu Y, Hainaut H, Xu Q. Mechanical stress-induced DNA damage and rac-p38MAPK signal pathways mediate p53-dependent apoptosis in vascular smooth muscle cells. FASEB J. 2002;16(11):1423–5.PubMed
28.
go back to reference Jufri NF, Mohamedali A, Avolio A, Baker MS. Mechanical stretch: physiological and pathological implications for human vascular endothelial cells. Vasc Cell. 2015;7:8.CrossRefPubMedPubMedCentral Jufri NF, Mohamedali A, Avolio A, Baker MS. Mechanical stretch: physiological and pathological implications for human vascular endothelial cells. Vasc Cell. 2015;7:8.CrossRefPubMedPubMedCentral
30.
go back to reference Gruden G, Thomas S, Burt D, Lane S, Chusney G, Sacks S, Viberti G. Mechanical stretch induces vascular permeability factor in human mesangial cells: mechanisms of signal transduction. Proc Natl Acad Sci U S A. 1997;94(22):12112–6.CrossRefPubMedPubMedCentral Gruden G, Thomas S, Burt D, Lane S, Chusney G, Sacks S, Viberti G. Mechanical stretch induces vascular permeability factor in human mesangial cells: mechanisms of signal transduction. Proc Natl Acad Sci U S A. 1997;94(22):12112–6.CrossRefPubMedPubMedCentral
31.
go back to reference Seko Y, Seko Y, Fujikura H, Pang J, Tokoro T, Shimokawa H. Induction of vascular endothelial growth factor after application of mechanical stress to retinal pigment epithelium of the rat in vitro. Invest Ophthalmol Vis Sci. 1999;40(13):3287–91.PubMed Seko Y, Seko Y, Fujikura H, Pang J, Tokoro T, Shimokawa H. Induction of vascular endothelial growth factor after application of mechanical stress to retinal pigment epithelium of the rat in vitro. Invest Ophthalmol Vis Sci. 1999;40(13):3287–91.PubMed
32.
go back to reference Zhou T, Hu Y, Chen Y, Zhou KK, Zhang B, Gao G, Ma JX. The pathogenic role of the canonical Wnt pathway in age-related macular degeneration. Invest Ophthalmol Vis Sci. 2010;51(9):4371–9.CrossRefPubMedPubMedCentral Zhou T, Hu Y, Chen Y, Zhou KK, Zhang B, Gao G, Ma JX. The pathogenic role of the canonical Wnt pathway in age-related macular degeneration. Invest Ophthalmol Vis Sci. 2010;51(9):4371–9.CrossRefPubMedPubMedCentral
33.
go back to reference Chen C, Krishnan R, Zhou E, Ramachandran A, Tambe D, Rajendran K, Adam RM, Deng L, Fredberg JJ. Fluidization and resolidification of the human bladder smooth muscle cell in response to transient stretch. PLoS One. 2010;5(8):e12035.CrossRefPubMedPubMedCentral Chen C, Krishnan R, Zhou E, Ramachandran A, Tambe D, Rajendran K, Adam RM, Deng L, Fredberg JJ. Fluidization and resolidification of the human bladder smooth muscle cell in response to transient stretch. PLoS One. 2010;5(8):e12035.CrossRefPubMedPubMedCentral
34.
go back to reference Zhou P, Kannan R, Spee C, Sreekumar PG, Dou G, Hinton DR. Protection of retina by alphaB crystallin in sodium iodate induced retinal degeneration. PLoS One. 2014;9(5):e98275.CrossRefPubMedPubMedCentral Zhou P, Kannan R, Spee C, Sreekumar PG, Dou G, Hinton DR. Protection of retina by alphaB crystallin in sodium iodate induced retinal degeneration. PLoS One. 2014;9(5):e98275.CrossRefPubMedPubMedCentral
35.
go back to reference Leung KW, Barnstable CJ, Tombran-Tink J. Bacterial endotoxin activates retinal pigment epithelial cells and induces their degeneration through IL-6 and IL-8 autocrine signaling. Mol Immunol. 2009;46(7):1374–86.CrossRefPubMed Leung KW, Barnstable CJ, Tombran-Tink J. Bacterial endotoxin activates retinal pigment epithelial cells and induces their degeneration through IL-6 and IL-8 autocrine signaling. Mol Immunol. 2009;46(7):1374–86.CrossRefPubMed
Metadata
Title
Cyclic stretch induced-retinal pigment epithelial cell apoptosis and cytokine changes
Authors
Shen Wu
Qingjun Lu
Ningli Wang
Jingxue Zhang
Qian Liu
Meng Gao
Jinqiu Chen
Wu Liu
Liang Xu
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Ophthalmology / Issue 1/2017
Electronic ISSN: 1471-2415
DOI
https://doi.org/10.1186/s12886-017-0606-0

Other articles of this Issue 1/2017

BMC Ophthalmology 1/2017 Go to the issue