Generic placeholder image

Current Proteomics

Author(s): Van-An Duong, Jeeyun Ahn, Na-Young Han, Jong-Moon Park, Jeong-Hun Mok, Tae Wan Kim* and Hookeun Lee*

DOI: 10.2174/1570164617666200302101442

DownloadDownload PDF Flyer Cite As
Proteomic Analysis of the Vitreous Body in Proliferative and Non-Proliferative Diabetic Retinopathy

Page: [143 - 152] Pages: 10

  • * (Excluding Mailing and Handling)

Abstract

Background: Diabetic Retinopathy (DR), one of the major microvascular complications commonly occurring in diabetic patients, can be classified into Proliferative Diabetic Retinopathy (PDR) and Non-Proliferative Diabetic Retinopathy (NPDR). Currently, available therapies are only targeted for later stages of the disease in which some pathologic changes may be irreversible. Thus, there is a need to develop new treatment options for earlier stages of DR through revealing pathological mechanisms of PDR and NPDR.

Objective: The purpose of this study was to characterize the proteomes of diabetes through quantitative analysis of PDR and NPDR.

Methods: Vitreous body was collected from three groups: control (non-diabetes mellitus), NPDR, and PDR. Vitreous proteins were digested to peptide mixtures and analyzed using LC-MS/MS. MaxQuant was used to search against the database and statistical analyses were performed using Perseus. Gene ontology analysis, related-disease identification, and protein-protein interaction were performed using the differential expressed proteins.

Results: Twenty proteins were identified as critical in PDR and NPDR. The NPDR group showed different expressions of kininogen-1, serotransferrin, ribonuclease pancreatic, osteopontin, keratin type II cytoskeletal 2 epidermal, and transthyretin. Also, prothrombin, signal transducer and activator of transcription 4, hemoglobin subunit alpha, beta, and delta were particularly up-regulated proteins for PDR group. The up-regulated proteins related to complement and coagulate cascades. Statherin was down-regulated in PDR and NPDR compared with the control group. Transthyretin was the unique protein that increased its abundance in NPDR compared with the PDR and control group.

Conclusion: This study confirmed the different expressions of some proteins in PDR and NPDR. Additionally, we revealed uniquely expressed proteins of PDR and NPDR, which would be differential biomarkers: prothrombin, alpha-2-HS-glycoprotein, hemoglobin subunit alpha, beta, and transthyretin.

Keywords: Non-proliferative diabetic retinopathy, proliferative diabetic retinopathy, vitreous body, proteomics, LC-MS/MS, gene ontology.

Graphical Abstract

[1]
Liu, Y.; Swearingen, R. Diabetic eye screening: Knowledge and perspectives from providers and patients. Curr. Diab. Rep., 2017, 17(10), 94.
[http://dx.doi.org/10.1007/s11892-017-0911-2] [PMID: 28856510]
[2]
Yau, J.W.Y.; Rogers, S.L.; Kawasaki, R.; Lamoureux, E.L.; Kowalski, J.W.; Bek, T.; Chen, S.J.; Dekker, J.M.; Fletcher, A.; Grauslund, J.; Haffner, S.; Hamman, R.F.; Ikram, M.K.; Kayama, T.; Klein, B.E.K.; Klein, R.; Krishnaiah, S.; Mayurasakorn, K.; O’Hare, J.P.; Orchard, T.J.; Porta, M.; Rema, M.; Roy, M.S.; Sharma, T.; Shaw, J.; Taylor, H.; Tielsch, J.M.; Varma, R.; Wang, J.J.; Wang, N.; West, S.; Xu, L.; Yasuda, M.; Zhang, X.; Mitchell, P.; Wong, T.Y. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care, 2012, 35(3), 556-564.
[http://dx.doi.org/10.2337/dc11-1909] [PMID: 22301125]
[3]
Cheung, N.; Mitchell, P.; Wong, T.Y. Diabetic retinopathy. Lancet, 2010, 376(9735), 124-136.
[http://dx.doi.org/10.1016/S0140-6736(09)62124-3] [PMID: 20580421]
[4]
Youngblood, H.; Robinson, R.; Sharma, A.; Sharma, S.S. Sharma. Proteomic biomarkers of retinal inflammation in diabetic retinopathy. Int. J. Mol. Sci., 2019, 20(19), 4755.
[http://dx.doi.org/10.3390/ijms20194755] [PMID: 31557880]
[5]
Gardner, T.W.J.R.; Davila, J.R. The neurovascular unit and the pathophysiologic basis of diabetic retinopathy. Graefes Arch. Clin. Exp. Ophthalmol., 2017, 255(1), 1-6.
[http://dx.doi.org/10.1007/s00417-016-3548-y] [PMID: 27832340]
[6]
Tikhonenko, M.; Lydic, T.A.; Wang, Y.; Chen, W.; Opreanu, M.; Sochacki, A.; McSorley, K.M.; Renis, R.L.; Kern, T.; Jump, D.B.; Reid, G.E.; Busik, J.V. Remodeling of retinal fatty acids in an animal model of diabetes.A decrease in long-chain polyunsaturated fatty acids is associated with a decrease in fatty acid elongases Elovl2 and Elovl4. Diabetes, 2010, 59(1), 219-227.
[7]
Lott, M.E.; Slocomb, J.E.; Gao, Z.; Gabbay, R.A.; Quillen, D.; Gardner, T.W.; Bettermann, K. Impaired coronary and retinal vasomotor function to hyperoxia in individuals with type 2 diabetes. Microvasc. Res., 2015, 101, 1-7.
[http://dx.doi.org/10.1016/j.mvr.2015.05.002] [PMID: 26002545]
[8]
Lott, M.E.J.; Slocomb, J.E.; Shivkumar, V.; Smith, B.; Gabbay, R.A.; Quillen, D.; Gardner, T.W.; Bettermann, K. Comparison of retinal vasodilator and constrictor responses in type 2 diabetes. Acta Ophthalmol., 2012, 90(6), e434-e441.
[http://dx.doi.org/10.1111/j.1755-3768.2012.02445.x] [PMID: 22682034]
[9]
Gardner, T.W.; Sundstrom, J.M. A proposal for early and personalized treatment of diabetic retinopathy based on clinical pathophysiology and molecular phenotyping. Vision Res., 2017, 139, 153-160.
[10]
Stitt, A.W.; Curtis, T.M.; Chen, M.; Medina, R.J.; McKay, G.J.; Jenkins, A.; Gardiner, T.A.; Lyons, T.J.; Hammes, H.P.; Simó, R.; Lois, N. The progress in understanding and treatment of diabetic retinopathy. Prog. Retin. Eye Res., 2016, 51, 156-186.
[11]
Loukovaara, S.; Nurkkala, H.; Tamene, F.; Gucciardo, E.; Liu, X.; Repo, P.; Lehti, K.; Varjosalo, M.M. Varjosalo. Quantitative proteomics analysis of vitreous humor from diabetic retinopathy patients. J. Proteome Res., 2015, 14(12), 5131-5143.
[http://dx.doi.org/10.1021/acs.jproteome.5b00900] [PMID: 26490944]
[12]
Li, J.; Lu, Q.; Lu, P. Quantitative proteomics analysis of vitreous body from type 2 diabetic patients with proliferative diabetic retinopathy. BMC Ophthalmol., 2018, 18(1), 151.
[http://dx.doi.org/10.1186/s12886-018-0821-3] [PMID: 29940965]
[13]
Chiang, S.Y.; Tsai, M.L.; Wang, C.Y.; Chen, A.; Chou, Y.C.; Hsia, C.W.; Wu, Y.F.; Chen, H.M.; Huang, T.H.; Chen, P.H.; Liu, H.T.; Shui, H.A. Proteomic analysis and identification of aqueous humor proteins with a pathophysiological role in diabetic retinopathy. J. Proteomics, 2012, 75(10), 2950-2959.
[http://dx.doi.org/10.1016/j.jprot.2011.12.006] [PMID: 22200677]
[14]
Kim, T.; Kim, S.J.; Kim, K.; Kang, U-B.; Lee, C.; Park, K.S.; Yu, H.G.; Kim, Y. Profiling of vitreous proteomes from proliferative diabetic retinopathy and nondiabetic patients. Proteomics, 2007, 7(22), 4203-4215.
[http://dx.doi.org/10.1002/pmic.200700745] [PMID: 17955474]
[15]
Balaiya, S.; Zhou, Z. Characterization of vitreous and aqueous proteome in humans with proliferative diabetic retinopathy and its clinical correlation. Proteomics Insights, 2017, 8(1) 1-10.
[16]
Gao, B.B.; Chen, X.; Timothy, N.; Aiello, L.P.; Feener, E.P. Characterization of the vitreous proteome in diabetes without diabetic retinopathy and diabetes with proliferative diabetic retinopathy. J. Proteome Res., 2008, 7(6), 2516-2525.
[http://dx.doi.org/10.1021/pr800112g] [PMID: 18433156]
[17]
Cabello-Ruiz, D.E.; Torres-de la Cruz, V.M.; Rivas-Morales, C.; Molina-Salinas, G.M.; Núñez-González, M.A.; Verde-Star, M.J.; Leos-Rivas, C. Proteomic analysis of a bioactive aloe vera extract. Curr. Proteomics, 2019, 16(3), 181-187.
[18]
Farooq, Q.A.; Haq, N.; Aziz, A.; Aimen, S.; Haq, M.I. Mass spectrometry for proteomics and recent developments in ESI, MALDI and other ionization methodologies. Curr. Proteomics, 2019, 16(4), 267-276.
[http://dx.doi.org/10.2174/1570164616666190204154653]
[19]
Rajdeep, D.; Nisha, D.S.; Surya Kant, C.; Sethumadhavan, M.; Anura, V.K.M.; Kumar, A. Analysis of extracellular proteome of staphylococcus aureus : a mass spectrometry based proteomics method of exotoxin characterisation. Curr. Proteomics, 2020, 17(1), 3-9.
[http://dx.doi.org/10.2174/1570164616666190204160627]
[20]
Liu, Y.P.; Hu, S.W.; Wu, Z.F.; Mei, L.X.; Lang, P.; Lu, X.H. Proteomic analysis of human serum from diabetic retinopathy. Int. J. Ophthalmol., 2011, 4(6), 616-622.
[PMID: 22553731]
[21]
Kim, K.; Kim, S.J.; Han, D.; Jin, J.; Yu, J.; Park, K.S.; Yu, H.G.; Kim, Y. Verification of multimarkers for detection of early stage diabetic retinopathy using multiple reaction monitoring. J. Proteome Res., 2013, 12(3), 1078-1089.
[http://dx.doi.org/10.1021/pr3012073] [PMID: 23368427]
[22]
Hagan, S.; Martin, E.; Enríquez-de-Salamanca, A. Tear fluid biomarkers in ocular and systemic disease: potential use for predictive, preventive and personalised medicine. EPMA J., 2016, 7(1), 15-15.
[http://dx.doi.org/10.1186/s13167-016-0065-3] [PMID: 27413414]
[23]
Csősz, É.; Boross, P.; Csutak, A.; Berta, A.; Tóth, F.; Póliska, S.; Török, Z.; Tőzsér, J. Quantitative analysis of proteins in the tear fluid of patients with diabetic retinopathy. J. Proteomics, 2012, 75(7), 2196-2204.
[http://dx.doi.org/10.1016/j.jprot.2012.01.019] [PMID: 22300579]
[24]
Kim, K.; Kim, S.J.; Yu, H.G.; Yu, J.; Park, K.S.; Jang, I.J.; Kim, Y. Verification of biomarkers for diabetic retinopathy by multiple reaction monitoring. J. Proteome Res., 2010, 9(2), 689-699.
[http://dx.doi.org/10.1021/pr901013d] [PMID: 20020744]
[25]
Kanehisa, M.; Furumichi, M.; Tanabe, M.; Sato, Y.; Morishima, K. KEGG: new perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res., 2017, 45(D1), D353-D361.
[http://dx.doi.org/10.1093/nar/gkw1092] [PMID: 27899662]
[26]
Kanehisa, M.; Sato, Y.; Furumichi, M.; Morishima, K.; Tanabe, M. New approach for understanding genome variations in KEGG. Nucleic Acids Res., 2019, 47(D1), D590-D595.
[http://dx.doi.org/10.1093/nar/gky962] [PMID: 30321428]
[27]
Kanehisa, M.; Sato, Y.; Kawashima, M.; Furumichi, M.; Tanabe, M. KEGG as a reference resource for gene and protein annotation. Nucleic Acids Res., 2016, 44(D1), D457-D462.
[http://dx.doi.org/10.1093/nar/gkv1070] [PMID: 26476454]
[28]
Jin, J.; Min, H.; Kim, S.J.; Oh, S.; Kim, K.; Yu, H.G.; Park, T.Y. Kim. Development of diagnostic biomarkers for detecting diabetic retinopathy at early stages using quantitative proteomics. J. Diabetes Res., 2016, 2016(22), 6571976.
[29]
Wang, H.; Feng, L.; Hu, J.; Xie, C.; Wang, F. Differentiating vitreous proteomes in proliferative diabetic retinopathy using high-performance liquid chromatography coupled to tandem mass spectrometry. Exp. Eye Res., 2013, 108, 110-119.
[30]
Yamane, K.; Minamoto, A.; Yamashita, H.; Takamura, H.; Miyamoto-Myoken, Y.; Yoshizato, K.; Nabetani, T.; Tsugita, A.H.K. Mishima. Proteome analysis of human vitreous proteins. Mol. Cell. Proteomics, 2003, 2(11), 1177-1187.
[http://dx.doi.org/10.1074/mcp.M300038-MCP200]
[31]
Shitama, T.; Hayashi, H.; Noge, S.; Uchio, E.; Oshima, K.; Haniu, H.; Takemori, N.; Komori, N.; Matsumoto, H. Proteome profiling of vitreoretinal diseases by cluster analysis. Proteomics Clin. Appl., 2008, 2(9), 1265-1280.
[http://dx.doi.org/10.1002/prca.200800017] [PMID: 19081814]
[32]
Simó, R.; Higuera, M.; García-Ramírez, M.; Canals, F.; García-Arumí, J.; Hernández, C. Elevation of apolipoprotein A-I and apolipoprotein H levels in the vitreous fluid and overexpression in the retina of diabetic patients. Arch. Ophthalmol., 2008, 126(8), 1076-1081.
[http://dx.doi.org/10.1001/archopht.126.8.1076] [PMID: 18695102]
[33]
Schori, C.; Trachsel, C.; Grossmann, J.; Zygoula, I.; Barthelmes, D.; Grimm, C.C. Grimm. The proteomic landscape in the vitreous of patients with age-related and diabetic retinal disease. Invest. Ophthalmol. Vis. Sci., 2018, 59(4), AMD31-AMD40.
[http://dx.doi.org/10.1167/iovs.18-24122] [PMID: 30025106]
[34]
Kim, S.J.; Kim, S.; Park, J.; Lee, H.K.; Park, K.S.; Yu, H.G.; Kim, Y. Differential expression of vitreous proteins in proliferative diabetic retinopathy. Curr. Eye Res., 2006, 31(3), 231-240.
[http://dx.doi.org/10.1080/02713680600557030] [PMID: 16531280]
[35]
Kim, H.J.; Kim, P.K.; Yoo, H.S.; Kim, C.W. Comparison of tear proteins between healthy and early diabetic retinopathy patients. Clin. Biochem., 2012, 45(1-2), 60-67.
[http://dx.doi.org/10.1016/j.clinbiochem.2011.10.006] [PMID: 22040812]
[36]
Cehofski, L.J.; Kruse, A.; Bøgsted, M.; Magnusdottir, S.O.; Stensballe, A.; Honoré, B.; Vorum, H. Retinal proteome changes following experimental branch retinal vein occlusion and intervention with ranibizumab. Experiment. Eye Res., 2016, 152, 49-56.
[37]
Cehofski, L.J.; Mandal, N.; Honoré, B.; Vorum, H. Analytical platforms in vitreoretinal proteomics. Bioanalysis, 2014, 6(22), 3051-3066.
[http://dx.doi.org/10.4155/bio.14.227] [PMID: 25496257]
[38]
Walia, S.; Clermont, A.C.; Gao, B-B.; Aiello, L.P.; Feener, E.P. Vitreous proteomics and diabetic retinopathy. Semin. Ophthalmol., 2010, 25(5-6), 289-294.
[http://dx.doi.org/10.3109/08820538.2010.518912] [PMID: 21091014]
[39]
Perez-Riverol, Y.; Csordas, A.; Bai, J.; Bernal-Llinares, M.; Hewapathirana, S.; Kundu, D.J.; Inuganti, A.; Griss, J.; Mayer, G.; Eisenacher, M.; Pérez, E.; Uszkoreit, J.; Pfeuffer, J.; Sachsenberg, T.; Yilmaz, S.; Tiwary, S.; Cox, J.; Audain, E.; Walzer, M.; Jarnuczak, A.F.; Ternent, T.; Brazma, A.; Vizcaíno, J.A. The PRIDE database and related tools and resources in 2019: improving support for quantification data. Nucleic Acids Res., 2019, 47(D1), D442-D450.
[http://dx.doi.org/10.1093/nar/gky1106] [PMID: 30395289]