BMP‑6 protects retinal pigment epithelial cells from oxidative stress‑induced injury by inhibiting the MAPK signaling pathways

Chen,Li; Liu,Ming; Luan,Yan; Liu,Yingfei; Zhang,Zhichao; Ma,Bo; Liu,Xuan; Liu,Yong

doi:10.3892/ijmm.2018.3675

BMP‑6 protects retinal pigment epithelial cells from oxidative stress‑induced injury by inhibiting the MAPK signaling pathways

Authors:
- Li Chen
- Ming Liu
- Yan Luan
- Yingfei Liu
- Zhichao Zhang
- Bo Ma
- Xuan Liu
- Yong Liu
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Affiliations: Department of Ophthalmology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China, Department of Ophthalmology, The First Hospital of Xi'an, Xi'an, Shaanxi 710002, P.R. China, Institute of Neurobiology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, P.R. China
Published online on: May 14, 2018 https://doi.org/10.3892/ijmm.2018.3675
Pages: 1096-1105

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Abstract

Worldwide, neovascular age‑related macular degeneration (nAMD) is one of the most common causes of blindness in the elderly. In particular, degeneration of retinal pigment epithelial (RPE) cells represents the main pathological process in the development of nAMD, and oxidative stress serves a major role. The present study aimed to investigate the association between bone morphogenetic protein 6 (BMP‑6) and nAMD. BMP‑6 concentration was significantly reduced in patients with wet nAMD compared with in the control group. Furthermore, the present study investigated the protective effects of BMP‑6 on RPE cells following oxidative stress‑induced injury. Cell Counting Kit‑8 assay and terminal deoxynucleotidyl transferase dUTP nick‑end labeling staining demonstrated that BMP‑6 increased RPE cell viability, which was decreased following treatment with hydrogen peroxide (H2O2), and reduced H2O2‑induced apoptosis. In addition, western blotting revealed that BMP‑6 reversed the decrease in pro‑caspase‑3 levels and the dysregulation of the B‑cell lymphoma 2 (Bcl‑2)/Bcl‑2‑associated X protein (Bax) balance caused by H2O2. In addition, alterations in c‑Jun N‑terminal protein kinase (JNK) and p38 mitogen‑activated protein kinase (MAPK) expression were examined, and pretreatment with BMP‑6 was demonstrated to reduce H2O2‑induced activation of JNK and p38 MAPK. Conversely, the effects of BMP‑6 were attenuated by its inhibitor noggin. In conclusion, the present study demonstrated that BMP‑6 may protect RPE cells from oxidative stress injury to a certain extent, which may be associated with alterations in the MAPK signaling pathway. However, the specific mechanism of action underlying this effect requires further investigation. Overall, the present study laid a foundation for exploring novel nAMD treatment methods.

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1	Klettner A: Age-related macular degeneration-biology and treatment. Med Monatsschr Pharm. 38:258–66. 2015.In German.
2	Liu C, Cao L, Yang S, Xu L, Liu P, Wang F and Xu D: Subretinal injection of amyloid-β peptide accelerates RPE cell senescence and retinal degeneration. Int J Mol Med. 35:169–76. 2015. View Article : Google Scholar
3	Zhu Y, Zhang L, Lu Q, Gao Y, Cai Y, Sui A, Su T, Shen X and Xie B: Identification of different macrophage subpopulations with distinct activities in a mouse model of oxygen-induced retinopathy. Int J Mol Med. 40:281–292. 2017. View Article : Google Scholar : PubMed/NCBI
4	Hadziahmetovic M, Song Y, Wolkow N, Iacovelli J, Kautz J, Roth MP and Dunaief JL: Bmp6 regulates retinal iron homeostasis and has altered expression in age-related macular degeneration. Am J Pathol. 179:335–348. 2011. View Article : Google Scholar : PubMed/NCBI
5	Andriopoulos B Jr, Corradini E, Xia Y, Faasse SA, Chen S, Grgurevic L, Knutson MD, Pietrangelo A, Vukicevic S, Lin HY and Babitt JL: BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat Genet. 41:482–487. 2009. View Article : Google Scholar : PubMed/NCBI
6	Haynes T, Gutierrez C, Aycinena JC, Tsonis PA and Del Rio-Tsonis K: BMP signaling mediates stem/progenitor cell-induced retina regeneration. Proc Natl Acad Sci USA. 104:20380–20385. 2007. View Article : Google Scholar : PubMed/NCBI
7	Canali S, Zumbrennen-Bullough KB, Core AB, Wang CY, Nairz M, Boulery R, Swirski FK and Babbit JL: Endothelial cells produce bone morphogenetic protein 6 required for iron homeostasis in mice. Blood. 129:405–414. 2017. View Article : Google Scholar :
8	McCubrey JA, Lahair MM and Franklin RA: Reactive oxygen species-induced activation of the MAP kinase signaling pathways. Antioxid Redox Signal. 8:1775–1789. 2006. View Article : Google Scholar : PubMed/NCBI
9	Ki YW, Park JH, Lee JE, Shin IC and Koh HC: JNK and p38 MAPK regulate oxidative stress and the inflammatory response in chlorpyrifos-induced apoptosis. Toxicol Lett. 218:235–245. 2013. View Article : Google Scholar : PubMed/NCBI
10	Feligioni M, Brambilla E, Camassa A, Sclip A, Arnaboldi A, Morelli F, Antoniou X and Borsello T: Crosstalk between JNK and SUMO signaling pathways: deSUMOylation is protective against H₂O₂-induced cell injury. PLoS One. 6:e281852011. View Article : Google Scholar
11	Shepherd TG, Heriault BL and Naehtigal MW: Autocrine BMP4 signalling regulates ID3 Proto-oncogene expression in human ovarian cancer cells. Gene. 414:95–105. 2008. View Article : Google Scholar : PubMed/NCBI
12	Piubelli C, Castagna A, Marchi G, Rizzi M, Busti F, Badar S, Marchetti M, De Gobbi M, Roetto A, Xumerle L, et al: Identification of new BMP6 pro-peptide mutations in patients with iron overload. Am J Hematol. 92:562–568. 2017. View Article : Google Scholar : PubMed/NCBI
13	Yan J, Yang S, Zhang J, Zhai C and Zhu T: BMP6 attenuates oxidant injury in HK-2 cells via Smad-dependent HO-1 induction. Free Radic Biol Med. 46:1275–1282. 2009. View Article : Google Scholar : PubMed/NCBI
14	Meynard D, Kautz L, Darnaud V, Canonne-Hergaux F, Coppin H and Roth MP: Lack of the bone morphogenetic protein BMP6 induces massive iron overload. Nat Genet. 41:478–481. 2009. View Article : Google Scholar : PubMed/NCBI
15	Bhuto I and Luty G: Understanding age-related macular degeneration (AMD): Relationships between the photoreceptor/retinal pigment epithelium/Bruch's membrane/choriocapillaris complex. Mol Aspects Med. 33:295–317. 2012. View Article : Google Scholar
16	Haudek VJ, Gundacker NC, Slany A, Wimmersion H, Bayer E, Pablé K and Gerner C: Consequences of acute and chronic oxidative stress upon the expression pattern of proteins in peripheral blood mononuclear cells. J Proteome Res. 7:5138–5147. 2008. View Article : Google Scholar
17	Zhao L, Li Y, Song D, Song Y, Theurl M, Wang C, Cwanger A, Su G and Dunaief JL: A high serum iron level causes mouse retinal iron accumulation despite an intact blood-retinal barrier. Am J Pathol. 184:2862–2867. 2014. View Article : Google Scholar : PubMed/NCBI
18	Tu G, Zhang YF, Wei W, Li L, Zhang Y, Yang J and Xing Y: Allicin attenuates H₂O₂-induced cytotoxicity in retinal pigmented epithelial cells by regulating the levels of reactive oxygen species. Mol Med Rep. 13:2320–2326. 2016. View Article : Google Scholar : PubMed/NCBI
19	Cia D, Vergaud-Gauduchon J, Jacquemot N and Doly M: Epigallocatechin gallate (EGCG) prevents H₂O₂-induced oxidative stress in primary rat retinal pigment epithelial cells. Curr Eye Res. 39:944–952. 2014. View Article : Google Scholar : PubMed/NCBI
20	Tamm C, Zhivotovsky B and Ceccatelli S: Caspase-2 activation in neural stem cells undergoing oxidative stress-induced apoptosis. Apoptosis. 13:354–363. 2008. View Article : Google Scholar : PubMed/NCBI
21	Savory J, Rao JK, Huang Y, Letada PR and Herman MM: Age-related hippocampal changes in Bcl-2: Bax ratio, oxidative stress, redox-active iron and apoptosis associated with aluminum-induced neurodegenerati: Increased susceptibility with aging. Neurotoxicology. 20:805–817. 1999.PubMed/NCBI
22	Naderi J, Hung M and Pandey S: Oxidative stress-induced apoptosis in dividing fibroblasts involves activation of p38 MAP kinase and over-expression of Bax: Resistance of quiescent cells to oxidative stress. Apoptosis. 8:91–100. 2003. View Article : Google Scholar : PubMed/NCBI
23	Snigdha S, Smith ED, Prieto GA and Cotman CW: Caspase-3 activation as a bifurcation point between plasticity and cell death. Neurosci Bull. 28:14–24. 2012. View Article : Google Scholar : PubMed/NCBI
24	Hoshyar R, Bathaie SZ and Sadeghizadeh M: Crocin triggers the apoptosis through increasing the Bax/Bcl-2 ratio and caspase activation in human gastric adenocarcinoma, AGS, cells. DNA Cell Biol. 32:50–57. 2013. View Article : Google Scholar : PubMed/NCBI
25	Rosen RB, Hu DN, Chen M, McCormick SA, Walsh J and Roberts JE: Effects of melatonin and its receptor antagonist on retinal pigment epithelial cells against hydrogen peroxide damage. Mol Vis. 18:1640–1648. 2012.PubMed/NCBI
26	Wang ZY, Shen LJ, Tu L, Hu DN, Liu GY, Zhou ZL, Lin Y, Chen LH and Qu J: Erythropoietin protects retinal pigment epithelial cells from oxidative damage. Free Radical Biol Med. 46:1032–1041. 2009. View Article : Google Scholar
27	Paeng SH, Jung WK, Park WS, Lee DS, Kim GY, Choi YH, Seo SK, Jang WH, Choi JS, Lee YM, et al: Caffeic acid phenethyl ester reduces the secretion of vascular endothelial growth factor through the inhibition of the ROS, PI3K and HIF-1α signaling pathways in human retinal pigment epithelial cells under hypoxic conditions. Int J Mol Med. 35:1419–1426. 2015. View Article : Google Scholar : PubMed/NCBI
28	Bokara KK, Kwon KH, Nho Y, Lee WT, Park KA and Lee JE: Retroviral expression of arginine decarboxylase attenuates oxidative burden in mouse cortical neural stem cells. Stem Cells Dev. 20:527–537. 2011. View Article : Google Scholar
29	Sekine Y, Takeda K and Ichijo H: The ASK1-MAP kinase signaling in ER stress and neurodegenerative diseases. Curr Mol Med. 6:87–97. 2006. View Article : Google Scholar : PubMed/NCBI
30	Kamata H, Honda S, Maeda S, Chang L, Hirata H and Karin M: Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell. 120:649–661. 2005. View Article : Google Scholar : PubMed/NCBI
31	Kim JH, Choi W, Lee JH, Jeon SJ, Choi YH, Kim BW, Chang HI and Nam SW: Astaxanthin inhibits H₂O₂-mediated apoptotic cell death in mouse neural progenitor cells via modulation of P38 and MEK signaling pathways. J Microbiol Biotechnol. 19:1355–1363. 2009.PubMed/NCBI
32	Wang C, Hao Z, Zhou J, Zhang J, Sun Y and Liang C: Rutaecarpine alleviates renal ischemia reperfusion injury in rats by suppressing the JNK/p38 MAPK signaling pathway and interfering with the oxidative stress response. Mol Med Rep. 16:922–928. 2017. View Article : Google Scholar : PubMed/NCBI
33	Yuen HF, McCrudden CM, Grills C, Zhang SD, Huang YH, Chan KK, Chan YP, Wong ML, Law S, Srivastava G, et al: Combinatorial use of bone morphogenetic protein 6, noggin and SOST significantly predicts cancer progression. Cancer Sci. 103:1145–1154. 2012. View Article : Google Scholar : PubMed/NCBI
34	Song K, Krause C, Shi S, Patterson M, Suto R, Grgurevic L, Vukicevic S, van Dinther M, Falb D, Ten Dijke P and Alaoui-Ismaili MH: Identification of a key residue mediating bone morphogenetic protein (BMP)-6 resistance to noggin inhibition allows for engineered BMPs with superior agonist activity. J Biol Chem. 285:12169–12180. 2010. View Article : Google Scholar : PubMed/NCBI
35	Abell AN, Granger DA and Johnson GL: MEKK4 stimulation of p38 and JNK activity is negatively regulated by GSK3beta. J Biol Chem. 282:30476–30484. 2007. View Article : Google Scholar : PubMed/NCBI
36	Sun G, Li Z, Wang X, Tang W and Wei Y: Modulation of MAPK and Akt signaling pathways in proximal segment of injured sciatic nerves. Neurosci Lett. 534:205–210. 2013. View Article : Google Scholar : PubMed/NCBI
37	Zhang Y, Liu Y, Hang A, Phan E and Wildsoet CF: Differential gene expression of BMP2 and BMP receptors in chick retina & choroid induced by imposed optical defocus. Vis Neurosci. 33:E0152016. View Article : Google Scholar
38	Tawfik A, Gnana-Prakasam JP, Smith SB and Ganapathy V: Deletion of hemojuvelin, an iron-regulatory protein, in mice results in abnormal angiogenesis and vasculogenesis in retina along with reactive gliosis. Invest Ophthalmol Vis Sci. 55:3616–3625. 2014. View Article : Google Scholar : PubMed/NCBI
39	Bandyopadhyay A, Yadav PS and Prashar P: BMP signaling in development and diseases: A pharmacological perspective. Biochem Pharmacol. 85:857–864. 2013. View Article : Google Scholar : PubMed/NCBI
40	Arjunan P, Gnanaprakasam JP, Ananth S, Romej MA, Rajalakshmi VK, Prasad PD, Martin PM, Gurusamy M, Thangaraju M, Bhutia YD and Ganapathy V: Increased retinal expression of the pro-angiogenic receptor GPR91 via BMP6 in a mouse model of juvenile hemochromatosis. Invest Ophthalmol Vis Sci. 57:1612–1619. 2016. View Article : Google Scholar : PubMed/NCBI