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Transcriptional patterns of human retinal pigment epithelial cells under protracted high glucose

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Abstract

Background

The retinal pigment epithelium (RPE) is essential for retinal homeostasis. Comprehensively exploring the transcriptional patterns of diabetic human RPE promotes the understanding of diabetic retinopathy (DR).

Methods and Results

A total of 4125 differentially expressed genes (DEGs) were screened out from the human primary RPE cells subjected to prolonged high glucose (HG). The subsequent bioinformatics analysis is divided into 3 steps. In Step 1, 21 genes were revealed by intersecting the enriched genes from the KEGG, WIKI, and Reactome databases. In Step 2, WGCNA was applied and intersected with the DEGs. Further intersection based on the enrichments with the GO biological processes, GO cellular components, and GO molecular functions databases screened out 12 candidate genes. In Step 3, 13 genes were found to be simultaneously up-regulated in the DEGs and a GEO dataset involving human diabetic retinal tissues. VEGFA and ERN1 were the 2 starred genes finally screened out by overlapping the 3 Steps.

Conclusion

In this study, multiple genes were identified as crucial in the pathological process of RPE under protracted HG, providing potential candidates for future researches on DR. The current study highlights the importance of RPE in DR pathogenesis.

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Data availability

All data supporting the findings of this study are available within the paper and its Supplementary Information.

References

  1. Campochiaro PA, Akhlaq A (2021) Sustained suppression of VEGF for treatment of retinal/choroidal vascular diseases. Prog Retin Eye Res 83:100921. https://doi.org/10.1016/j.preteyeres.2020.100921

    Article  CAS  PubMed  Google Scholar 

  2. Pan WW, Lin F, Fort PE (2021) The innate immune system in diabetic retinopathy. Prog Retin Eye Res 84:100940. https://doi.org/10.1016/j.preteyeres.2021.100940

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Tonade D, Kern TS (2021) Photoreceptor cells and RPE contribute to the development of diabetic retinopathy. Prog Retin Eye Res 83:100919. https://doi.org/10.1016/j.preteyeres.2020.100919

    Article  PubMed  Google Scholar 

  4. Strauss O (2005) The retinal pigment epithelium in visual function. Physiol Rev 85:845–881. https://doi.org/10.1152/physrev.00021.2004

    Article  CAS  PubMed  Google Scholar 

  5. Kwon W, Freeman SA (2020) Phagocytosis by the retinal pigment epithelium: recognition, resolution. Recycling Front Immunol 11:604205. https://doi.org/10.3389/fimmu.2020.604205

    Article  CAS  PubMed  Google Scholar 

  6. Chiu CC, Cheng KC, Lin YH, He CX, Bow YD, Li CY, Wu CY, Wang HD, Sheu SJ (2023) Prolonged exposure to high glucose induces premature senescence through oxidative stress and autophagy in retinal pigment epithelial cells. Arch Immunol Ther Exp (Warsz) 71:21. https://doi.org/10.1007/s00005-023-00686-9

    Article  CAS  PubMed  Google Scholar 

  7. Singh LP, Yumnamcha T, Devi TS (2021) Mitophagy, ferritinophagy and ferroptosis in retinal pigment epithelial cells under high glucose conditions: implications for diabetic retinopathy and age-related retinal diseases. JOJ Ophthalmol 8:77–85

    PubMed  PubMed Central  Google Scholar 

  8. Zhang Y, Xi X, Mei Y, Zhao X, Zhou L, Ma M, Liu S, Zha X, Yang Y (2019) High-glucose induces retinal pigment epithelium mitochondrial pathways of apoptosis and inhibits mitophagy by regulating ROS/PINK1/Parkin signal pathway. Biomed Pharmacother 111:1315–1325. https://doi.org/10.1016/j.biopha.2019.01.034

    Article  CAS  PubMed  Google Scholar 

  9. Huang C, Qi P, Cui H, Lu Q, Gao X (2022) CircFAT1 regulates retinal pigment epithelial cell pyroptosis and autophagy via mediating m6A reader protein YTHDF2 expression in diabetic retinopathy. Exp Eye Res 222:109152. https://doi.org/10.1016/j.exer.2022.109152

    Article  CAS  PubMed  Google Scholar 

  10. Bang E, Park C, Hwangbo H, Shim JH, Leem SH, Hyun JW, Kim GY and Choi YH (2023) Spermidine attenuates high glucose-induced oxidative damage in retinal pigment epithelial cells by inhibiting production of ROS and NF-κB/NLRP3 inflammasome pathway. Int J Mol Sci 24. https://doi.org/10.3390/ijms241310550

  11. Salero E, Blenkinsop TA, Corneo B, Harris A, Rabin D, Stern JH, Temple S (2012) Adult human RPE can be activated into a multipotent stem cell that produces mesenchymal derivatives. Cell Stem Cell 10:88–95. https://doi.org/10.1016/j.stem.2011.11.018

    Article  CAS  PubMed  Google Scholar 

  12. Huang H, Zhu X, Cheng H, Kuang X, Long C, Deng X, Zou Y, Zhang H, Xing Y, Ling X, Wang R, Tang H, Du H, Shi K, Wang L, Yan J, Shen H (2021) 2,3,5,6-Tetramethylpyrazine protects retinal photoreceptors against endoplasmic reticulum stress by modulating ATF4-mediated inhibition of PRP aggregation. J Mol Med (Berl) 99:383–402. https://doi.org/10.1007/s00109-020-02017-3

    Article  CAS  PubMed  Google Scholar 

  13. Leek JT, Johnson WE, Parker HS, Jaffe AE, Storey JD (2012) The SVA package for removing batch effects and other unwanted variation in high-throughput experiments. Bioinformatics 28:882–883. https://doi.org/10.1093/bioinformatics/bts034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, Smyth GK (2015) Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 43:e47. https://doi.org/10.1093/nar/gkv007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Langfelder P, Horvath S (2008) WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics 9:559. https://doi.org/10.1186/1471-2105-9-559

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Li Y, Chen D, Sun L, Wu Y, Zou Y, Liang C, Bao Y, Yi J, Zhang Y, Hou J, Li Z, Yu F, Huang Y, Yu C, Liu L, Liu Z, Zhang Y, Li Y (2019) Induced expression of VEGFC, ANGPT, and EFNB2 and their receptors characterizes neovascularization in proliferative diabetic retinopathy. Invest Ophthalmol Vis Sci 60:4084–4096. https://doi.org/10.1167/iovs.19-26767

    Article  CAS  PubMed  Google Scholar 

  17. Hu Z, Mao X, Chen M, Wu X, Zhu T, Liu Y, Zhang Z, Fan W, Xie P, Yuan S, Liu Q (2022) Single-cell transcriptomics reveals novel role of microglia in fibrovascular membrane of proliferative diabetic retinopathy. Diabetes 71:762–773. https://doi.org/10.2337/db21-0551

    Article  CAS  PubMed  Google Scholar 

  18. Tarchick MJ, Bassiri P, Rohwer RM, Samuels IS (2016) Early functional and morphologic abnormalities in the diabetic nyxnob mouse retina. Invest Ophthalmol Vis Sci 57:3496–3508. https://doi.org/10.1167/iovs.15-18775

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wang XN, Li ST, Li W, Hua YJ, Wu Q (2018) The thickness and volume of the choroid, outer retinal layers and retinal pigment epithelium layer changes in patients with diabetic retinopathy. Int J Ophthalmol 11:1957–1962. https://doi.org/10.18240/ijo.2018.12.14

    Article  PubMed  PubMed Central  Google Scholar 

  20. Kang EC, Seo Y, Byeon SH (2016) Diabetic retinal pigment epitheliopathy: fundus autofluorescence and spectral-domain optical coherence tomography findings. Graefes Arch Clin Exp Ophthalmol 254:1931–1940. https://doi.org/10.1007/s00417-016-3336-8

    Article  CAS  PubMed  Google Scholar 

  21. Li M, Tian M, Wang Y, Ma H, Zhou Y, Jiang X and Liu Y (2023) Updates on RPE cell damage in diabetic retinopathy (Review). Mol Med Rep 28. https://doi.org/10.3892/mmr.2023.13072

  22. Ţălu Ş, Nicoara SD (2021) Malfunction of outer retinal barrier and choroid in the occurrence and progression of diabetic macular edema. World J Diabetes 12:437–452. https://doi.org/10.4239/wjd.v12.i4.437

    Article  PubMed  PubMed Central  Google Scholar 

  23. Xia T, Rizzolo LJ (2017) Effects of diabetic retinopathy on the barrier functions of the retinal pigment epithelium. Vision Res 139:72–81. https://doi.org/10.1016/j.visres.2017.02.006

    Article  PubMed  Google Scholar 

  24. Ravera S, Bertola N, Puddu A, Bruno S, Maggi D and Panfoli I (2023) Crosstalk between the rod outer segments and retinal pigmented epithelium in the generation of oxidative stress in an in vitro model. Cells 12. https://doi.org/10.3390/cells12172173

  25. Levine SR, Sapieha P, Dutta S, Sun JK, Gardner TW (2022) It is time for a moonshot to find “Cures” for diabetic retinal disease. Prog Retin Eye Res 90:101051. https://doi.org/10.1016/j.preteyeres.2022.101051

    Article  CAS  PubMed  Google Scholar 

  26. Donato L, Alibrandi S, Scimone C, Rinaldi C, Dascola A, Calamuneri A, D’Angelo R, Sidoti A (2022) The impact of modifier genes on cone-rod dystrophy heterogeneity: an explorative familial pilot study and a hypothesis on neurotransmission impairment. PLoS ONE 17:e0278857. https://doi.org/10.1371/journal.pone.0278857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Scimone C, Granata F, Longo M, Mormina E, Turiaco C, Caragliano AA, Donato L, Sidoti A and D’Angelo R (2020) Germline mutation enrichment in pathways controlling endothelial cell homeostasis in patients with brain arteriovenous malformation: implication for molecular diagnosis. Int J Mol Sci 21. doi: https://doi.org/10.3390/ijms21124321

  28. Hrdlickova R, Toloue M and Tian B (2017) RNA-Seq methods for transcriptome analysis. Wiley Interdiscip Rev RNA 8. https://doi.org/10.1002/wrna.1364

  29. Kirwin SJ, Kanaly ST, Hansen CR, Cairns BJ, Ren M, Edelman JL (2011) Retinal gene expression and visually evoked behavior in diabetic long evans rats. Invest Ophthalmol Vis Sci 52:7654–7663. https://doi.org/10.1167/iovs.10-6609

    Article  CAS  PubMed  Google Scholar 

  30. Fan S, Yang Z, Liu Y, Zhong J, Zhang S, Xiao Y, Liu X, Yi W, He C, Hu Y, Liu X (2021) Extensive sub-RPE complement deposition in a nonhuman primate model of early-stage diabetic retinopathy. Invest Ophthalmol Vis Sci 62:30. https://doi.org/10.1167/iovs.62.3.30

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wu J, Shi K, Zhang F and Sun X (2023) A 3-miRNA risk scoring signature in early diabetic retinopathy. J Clin Med 12. https://doi.org/10.3390/jcm12051777

  32. Apte RS, Chen DS, Ferrara N (2019) VEGF in signaling and disease: beyond discovery and development. Cell 176:1248–1264. https://doi.org/10.1016/j.cell.2019.01.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Arrigo A, Aragona E, Bandello F (2022) VEGF-targeting drugs for the treatment of retinal neovascularization in diabetic retinopathy. Ann Med 54:1089–1111. https://doi.org/10.1080/07853890.2022.2064541

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Noma H, Mimura T, Yasuda K, Shimura M (2014) Role of inflammation in diabetic macular edema. Ophthalmologica 232:127–135. https://doi.org/10.1159/000364955

    Article  CAS  PubMed  Google Scholar 

  35. Weigelt CM, Fuchs H, Schönberger T, Stierstorfer B, Strobel B, Lamla T, Ciossek T, Bakker RA, Redemann NH (2021) AAV-mediated expression of human VEGF, TNF-α, and IL-6 induces retinal pathology in mice. Transl Vis Sci Technol 10:15. https://doi.org/10.1167/tvst.10.11.15

    Article  PubMed  PubMed Central  Google Scholar 

  36. Campochiaro PA (2013) Ocular neovascularization J Mol Med (Berl) 91:311–321. https://doi.org/10.1007/s00109-013-0993-5

    Article  CAS  PubMed  Google Scholar 

  37. Li L, Wu D, Qin X, Mi LZ (2022) PDGF-D prodomain differentially inhibits the biological activities of PDGF-D and PDGF-B. J Mol Biol 434:167709. https://doi.org/10.1016/j.jmb.2022.167709

    Article  CAS  PubMed  Google Scholar 

  38. Lee-Rivera I, López E, Parrales A, Alvarez-Arce A, López-Colomé AM (2015) Thrombin promotes the expression of Ccnd1 gene in RPE cells through the activation of converging signaling pathways. Exp Eye Res 139:81–89. https://doi.org/10.1016/j.exer.2015.08.001

    Article  CAS  PubMed  Google Scholar 

  39. Wu JF, Liu Y, Gong SN, Zi XD, Tan YG (2023) Effects of vascular endothelial growth factor (VEGF) on the viability, apoptosis and steroidogenesis of yak (Bos grunniens) granulosa cells. Theriogenology 207:1–10. https://doi.org/10.1016/j.theriogenology.2023.05.020

    Article  CAS  PubMed  Google Scholar 

  40. Lee C, Chen R, Sun G, Liu X, Lin X, He C, Xing L, Liu L, Jensen LD, Kumar A, Langer HF, Ren X, Zhang J, Huang L, Yin X, Kim J, Zhu J, Huang G, Li J, Lu W, Chen W, Liu J, Hu J, Sun Q, Lu W, Fang L, Wang S, Kuang H, Zhang Y, Tian G, Mi J, Kang BA, Narazaki M, Prodeus A, Schoonjans L, Ornitz DM, Gariepy J, Eelen G, Dewerchin M, Yang Y, Ou JS, Mora A, Yao J, Zhao C, Liu Y, Carmeliet P, Cao Y, Li X (2023) VEGF-B prevents excessive angiogenesis by inhibiting FGF2/FGFR1 pathway. Signal Transduct Target Ther 8:305. https://doi.org/10.1038/s41392-023-01539-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zou X, Wu Z, Huang J, Liu P, Qin X, Chen L, Zhu W, Zhao Y, Li P, Song J, Yang GY, Mao Y (2018) The role of matrix metalloproteinase-3 in the doxycycline attenuation of intracranial venous hypertension-induced angiogenesis. Neurosurgery 83:1317–1327. https://doi.org/10.1093/neuros/nyx633

    Article  PubMed  Google Scholar 

  42. Saleh A, Stathopoulou MG, Dadé S, Ndiaye NC, Azimi-Nezhad M, Murray H, Masson C, Lamont J, Fitzgerald P, Visvikis-Siest S (2015) Angiogenesis related genes NOS3, CD14, MMP3 and IL4R are associated to VEGF gene expression and circulating levels in healthy adults. BMC Med Genet 16:90. https://doi.org/10.1186/s12881-015-0234-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ash D, Sudhahar V, Youn SW, Okur MN, Das A, O’Bryan JP, McMenamin M, Hou Y, Kaplan JH, Fukai T, Ushio-Fukai M (2021) The P-type ATPase transporter ATP7A promotes angiogenesis by limiting autophagic degradation of VEGFR2. Nat Commun 12:3091. https://doi.org/10.1038/s41467-021-23408-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Tan H, Chen J, Li Y, Li Y, Zhong Y, Li G, Liu L, Li Y (2022) Glabridin, a bioactive component of licorice, ameliorates diabetic nephropathy by regulating ferroptosis and the VEGF/Akt/ERK pathways. Mol Med 28:58. https://doi.org/10.1186/s10020-022-00481-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Ahluwalia TS, Troelsen JT, Balslev-Harder M, Bork-Jensen J, Thuesen BH, Cerqueira C, Linneberg A, Grarup N, Pedersen O, Hansen T, Dalgaard LT (2017) Carriers of a VEGFA enhancer polymorphism selectively binding CHOP/DDIT3 are predisposed to increased circulating levels of thyroid-stimulating hormone. J Med Genet 54:166–175. https://doi.org/10.1136/jmedgenet-2016-104084

    Article  CAS  PubMed  Google Scholar 

  46. Park M, Kim JY, Kim J, Lee JH, Kwon YG, Kim YM (2021) Low-dose metronomic doxorubicin inhibits mobilization and differentiation of endothelial progenitor cells through REDD1-mediated VEGFR-2 downregulation. BMB Rep 54:470–475. https://doi.org/10.5483/BMBRep.2021.54.9.096

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Langlais T, Pelizzari-Raymundo D, Mahdizadeh SJ, Gouault N, Carreaux F, Chevet E, Eriksson LA, Guillory X (2021) Structural and molecular bases to IRE1 activity modulation. Biochem J 478:2953–2975. https://doi.org/10.1042/BCJ20200919

    Article  CAS  PubMed  Google Scholar 

  48. Li J, Wang JJ, Yu Q, Wang M, Zhang SX (2009) Endoplasmic reticulum stress is implicated in retinal inflammation and diabetic retinopathy. FEBS Lett 583:1521–1527. https://doi.org/10.1016/j.febslet.2009.04.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Zhang SX, Wang JJ, Starr CR, Lee EJ, Park S, Zhylkibayev A, Medina A, Lin JH, Gorbatyuk M (2023) The endoplasmic reticulum: homeostasis and crosstalk in retinal health and disease. Prog Retin Eye Res 98:101231. https://doi.org/10.1016/j.preteyeres.2023.101231

    Article  CAS  PubMed  Google Scholar 

  50. Fan F, Liu F, Shen P, Tao L, Zhang H, Wu H (2023) Salvianolic acid B, a new type I IRE1 kinase inhibitor, abrogates AngII-induced angiogenesis by interacting with IRE1 in its active conformation. Clin Exp Pharmacol Physiol 50:82–95. https://doi.org/10.1111/1440-1681.13726

    Article  CAS  PubMed  Google Scholar 

  51. Wang J, Lee J, Liem D, Ping P (2017) HSPA5 Gene encoding Hsp70 chaperone BiP in the endoplasmic reticulum. Gene 618:14–23. https://doi.org/10.1016/j.gene.2017.03.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Fu D, Wu M, Zhang J, Du M, Yang S, Hammad SM, Wilson K, Chen J, Lyons TJ (2012) Mechanisms of modified LDL-induced pericyte loss and retinal injury in diabetic retinopathy. Diabetologia 55:3128–3140. https://doi.org/10.1007/s00125-012-2692-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Zou J, Fei Q, Xiao H, Wang H, Liu K, Liu M, Zhang H, Xiao X, Wang K, Wang N (2019) VEGF-A promotes angiogenesis after acute myocardial infarction through increasing ROS production and enhancing ER stress-mediated autophagy. J Cell Physiol 234:17690–17703. https://doi.org/10.1002/jcp.28395

    Article  CAS  PubMed  Google Scholar 

  54. Al-Keilani M, Alqudah MA, Almomani B, Alrjoub MM, Shhabat BA, Alzoubi K (2023) GRP78 is overexpressed in non-small cell lung cancer tissues and is associated with high VEGF expression in squamous cell carcinoma: a pilot study. Curr Cancer Drug Targets 23:805–816. https://doi.org/10.2174/1568009623666230418111020

    Article  CAS  PubMed  Google Scholar 

  55. Carr M, Gonzalez G, Martinelli A, Wastika CE, Ito K, Orba Y, Sasaki M, Hall WW, Sawa H (2019) Upregulated expression of the antioxidant sestrin 2 identified by transcriptomic analysis of Japanese encephalitis virus-infected SH-SY5Y neuroblastoma cells. Virus Genes 55:630–642. https://doi.org/10.1007/s11262-019-01683-x

    Article  CAS  PubMed  Google Scholar 

  56. Chen X, Shi C, He M, Xiong S, Xia X (2023) Endoplasmic reticulum stress: molecular mechanism and therapeutic targets. Signal Transduct Target Ther 8:352. https://doi.org/10.1038/s41392-023-01570-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Yogendran V, Mele L, Prysyazhna O, Budhram-Mahadeo VS (2023) Vascular dysfunction caused by loss of Brn-3b/POU4F2 transcription factor in aortic vascular smooth muscle cells is linked to deregulation of calcium signalling pathways. Cell Death Dis 14:770. https://doi.org/10.1038/s41419-023-06306-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Du Z, Hu J, Lin L, Liang Q, Sun M, Sun Z and Duan J (2022) Melatonin alleviates PM(2.5) -induced glucose metabolism disorder and lipidome alteration by regulating endoplasmic reticulum stress. J Pineal Res 73:e12823. https://doi.org/10.1111/jpi.12823

  59. Tousson-Abouelazm N, Papillon J, Guillemette J, Cybulsky AV (2020) Urinary ERdj3 and mesencephalic astrocyte-derived neutrophic factor identify endoplasmic reticulum stress in glomerular disease. Lab Invest 100:945–958. https://doi.org/10.1038/s41374-020-0416-5

    Article  CAS  PubMed  Google Scholar 

  60. Nakatsuka A, Yamaguchi S, Eguchi J, Kakuta S, Iwakura Y, Sugiyama H, Wada J (2021) A Vaspin-HSPA1L complex protects proximal tubular cells from organelle stress in diabetic kidney disease. Commun Biol 4:373. https://doi.org/10.1038/s42003-021-01902-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Zhu X, Chen X, Shen X, Liu Y, Fu W, Wang B, Zhao L, Yang F, Mo N, Zhong G, Jiang S, Yang Z (2024) PP4R1 accelerates the malignant progression of NSCLC via up-regulating HSPA6 expression and HSPA6-mediated ER stress. Biochim Biophys Acta Mol Cell Res 1871:119588. https://doi.org/10.1016/j.bbamcr.2023.119588

    Article  CAS  PubMed  Google Scholar 

  62. Liu CL, Zhong W, He YY, Li X, Li S, He KL (2016) Genome-wide analysis of tunicamycin-induced endoplasmic reticulum stress response and the protective effect of endoplasmic reticulum inhibitors in neonatal rat cardiomyocytes. Mol Cell Biochem 413:57–67. https://doi.org/10.1007/s11010-015-2639-0

    Article  CAS  PubMed  Google Scholar 

  63. Wang Z, Tan C, Duan C, Wu J, Zhou D, Hou L, Qian W, Han C, Hou X (2023) FUT2-dependent fucosylation of HYOU1 protects intestinal stem cells against inflammatory injury by regulating unfolded protein response. Redox Biol 60:102618. https://doi.org/10.1016/j.redox.2023.102618

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Zhang RK, Wang P, Lu YC, Lang L, Wang L, Lee SC (2019) Cadmium induces cell centrosome amplification via reactive oxygen species as well as endoplasmic reticulum stress pathway. J Cell Physiol 234:18230–18248. https://doi.org/10.1002/jcp.28455

    Article  CAS  PubMed  Google Scholar 

  65. Stitt AW, Curtis TM, Chen M, Medina RJ, McKay GJ, Jenkins A, Gardiner TA, Lyons TJ, Hammes HP, Simó R, Lois N (2016) The progress in understanding and treatment of diabetic retinopathy. Prog Retin Eye Res 51:156–186. https://doi.org/10.1016/j.preteyeres.2015.08.001

    Article  PubMed  Google Scholar 

  66. Li J, Chen K, Li X, Zhang X, Zhang L, Yang Q, Xia Y, Xie C, Wang X, Tong J, Shen Y (2023) Mechanistic insights into the alterations and regulation of the AKT signaling pathway in diabetic retinopathy. Cell Death Discov 9:418. https://doi.org/10.1038/s41420-023-01717-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Xia HQ, Yang JR, Zhang KX, Dong RL, Yuan H, Wang YC, Zhou H, Li XM (2022) Molecules related to diabetic retinopathy in the vitreous and involved pathways. Int J Ophthalmol 15:1180–1189. https://doi.org/10.18240/ijo.2022.07.20

    Article  PubMed  PubMed Central  Google Scholar 

  68. Li HY, Yuan Y, Fu YH, Wang Y, Gao XY (2020) Hypoxia-inducible factor-1α: a promising therapeutic target for vasculopathy in diabetic retinopathy. Pharmacol Res 159:104924. https://doi.org/10.1016/j.phrs.2020.104924

    Article  CAS  PubMed  Google Scholar 

  69. Karimi S, Arabi A, Shahraki T (2021) Alcohol and the eye. J Ophthalmic Vis Res 16:260–270. https://doi.org/10.18502/jovr.v16i2.9089

    Article  PubMed  PubMed Central  Google Scholar 

  70. Honoré B, Hajari JN, Pedersen TT, Ilginis T, Al-Abaiji HA, Lønkvist CS, Saunte JP, Olsen DA, Brandslund I, Vorum H, Slidsborg C (2024) Proteomic analysis of diabetic retinopathy identifies potential plasma-protein biomarkers for diagnosis and prognosis. Clin Chem Lab Med. https://doi.org/10.1515/cclm-2023-1128

    Article  PubMed  Google Scholar 

  71. Ikeda T, Nakamura K, Kida T, Oku H (2022) Possible roles of anti-type II collagen antibody and innate immunity in the development and progression of diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 260:387–403. https://doi.org/10.1007/s00417-021-05342-6

    Article  CAS  PubMed  Google Scholar 

  72. Ke D, Hong Y, Jiang X, Sun X (2022) Clinical features and vitreous biomarkers of early-onset type 2 diabetes mellitus complicated with proliferative diabetic retinopathy. Diabetes Metab Syndr Obes 15:1293–1303. https://doi.org/10.2147/DMSO.S362074

    Article  PubMed  PubMed Central  Google Scholar 

  73. Yoshida S, Kobayashi Y, Nakama T, Zhou Y, Ishikawa K, Arita R, Nakao S, Miyazaki M, Sassa Y, Oshima Y, Izuhara K, Kono T, Ishibashi T (2015) Increased expression of M-CSF and IL-13 in vitreous of patients with proliferative diabetic retinopathy: implications for M2 macrophage-involving fibrovascular membrane formation. Br J Ophthalmol 99:629–634. https://doi.org/10.1136/bjophthalmol-2014-305860

    Article  PubMed  Google Scholar 

  74. Guo C, Jiang D, Xu Y, Peng F, Zhao S, Li H, Jin D, Xu X, Xia Z, Che M, Lai M, Huang R, Wang H, Zheng C, Mao G (2022) High-coverage serum metabolomics reveals metabolic pathway dysregulation in diabetic retinopathy: a propensity score-matched study. Front Mol Biosci 9:822647. https://doi.org/10.3389/fmolb.2022.822647

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Wang R, Rao S, Zhong Z, Xiao K, Chen X, Sun X (2024) Emerging role of ferroptosis in diabetic retinopathy: a review. J Drug Target 1–11. https://doi.org/10.1080/1061186X.2024.2316775

  76. Vidhya S, Ramya R, Coral K, Sulochana KN, Bharathidevi SR (2018) Free amino acids hydroxyproline, lysine, and glycine promote differentiation of retinal pericytes to adipocytes: a protective role against proliferative diabetic retinopathy. Exp Eye Res 173:179–187. https://doi.org/10.1016/j.exer.2018.05.004

    Article  CAS  PubMed  Google Scholar 

  77. Roy S, Bae E, Amin S, Kim D (2015) Extracellular matrix, gap junctions, and retinal vascular homeostasis in diabetic retinopathy. Exp Eye Res 133:58–68. https://doi.org/10.1016/j.exer.2014.08.011

    Article  CAS  PubMed  Google Scholar 

  78. Kaur A, Kumar R, Sharma A (2024) Diabetic retinopathy leading to blindness- a review. Curr Diabetes Rev. https://doi.org/10.2174/0115733998274599231109034741

    Article  PubMed  Google Scholar 

  79. Al-Dwairi R, El-Elimat T, Aleshawi A, Al Sharie AH, Abu Mousa BM, Al Beiruti S, Alkazaleh A, Mohidat H (2023) Vitreous levels of vascular endothelial growth factor and platelet-derived growth factor in patients with proliferative diabetic retinopathy: a clinical correlation. Biomolecules 13. https://doi.org/10.3390/biom13111630

  80. Yang X, Huang Z, Xu M, Chen Y, Cao M, Yi G, Fu M (2023) Autophagy in the retinal neurovascular unit: new perspectives into diabetic retinopathy. J Diabetes 15:382–396. https://doi.org/10.1111/1753-0407.13373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Gao S, Zhang Y, Zhang M (2022) Targeting novel regulated cell death: pyroptosis, necroptosis, and ferroptosis in diabetic retinopathy. Front Cell Dev Biol 10:932886. https://doi.org/10.3389/fcell.2022.932886

    Article  PubMed  PubMed Central  Google Scholar 

  82. Lu C, Lan Q, Song Q, Yu X (2024) Identification and validation of ferroptosis-related genes for diabetic retinopathy. Cell Signal 113:110955. https://doi.org/10.1016/j.cellsig.2023.110955

    Article  CAS  PubMed  Google Scholar 

  83. Jacob M, Joseph M, Idiculla J (2023) Non-alcoholic fatty liver disease and diabetic retinopathy: is there an association? J Family Med Prim Care 12:2028–2031. https://doi.org/10.4103/jfmpc.jfmpc_2327_22

    Article  PubMed  PubMed Central  Google Scholar 

  84. Zong H, Ward M, Stitt AW (2011) AGEs, RAGE, and diabetic retinopathy. Curr Diab Rep 11:244–252. https://doi.org/10.1007/s11892-011-0198-7

    Article  PubMed  Google Scholar 

  85. Chen Y, Sun J, Zhang Z, Liu X, Wang Q, Yu Y (2022) The potential effects and mechanisms of hispidulin in the treatment of diabetic retinopathy based on network pharmacology. BMC Complement Med Ther 22:141. https://doi.org/10.1186/s12906-022-03593-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

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Funding

The work was supported by the National Natural Science Foundation of China (No. 81670885), the Natural Science Foundation of Guangdong Province of China (No. 2021A1515010513), and the Initial Scientific Research Fund of Doctors in Zhuzhou Hospital Affiliated to Xiangya School of Medicine Central South University (No. n/a).

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HH and HS conceived and designed the study. HH and JZ conducted the experiments. XK, FH, JY, and BL contributed to the data analysis. WL contributed to the image processing. HH and WL drafted the manuscript. All the authors revised the manuscript and approved its submission.

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Correspondence to Wei Liu or Huangxuan Shen.

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The authors have no relevant financial or non-financial interests to disclose.

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This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Institutional Review Board and the Medical Ethics Committee of State Key laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University (Approval NO. 2021KYPJ196).

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Informed consents for use in scientific research were obtained from the donors or donors’ families by the Eye Bank of Guangdong Province.

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Huang, H., Zeng, J., Kuang, X. et al. Transcriptional patterns of human retinal pigment epithelial cells under protracted high glucose. Mol Biol Rep 51, 477 (2024). https://doi.org/10.1007/s11033-024-09479-5

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