Journal of Molecular Neuroscience

, Volume 59, Issue 2, pp 232–240 | Cite as

Serum Response Factor Protects Retinal Ganglion Cells Against High-Glucose Damage

  • Yan Cao
  • Liang Wang
  • Junhong Zhao
  • Hongbing Zhang
  • Ying Tian
  • Houcheng Liang
  • Qiang MaEmail author


Serum response factor (SRF), which encodes the MADS-box family of related proteins, is a common transcription factor related to the expression of genes associated with cell survival. However, SRF’s role in retinal ganglion cells (RGCs) after high-glucose injury remains unclear. In this study, we investigate the protective role of SRF after high-glucose injury and its underlying mechanism. The in vitro RGC model subjected to high glucose was established by employing a 50 mmol/L glucose culture environment. As detected by real-time quantitative PCR and Western blot, SRF was significantly upregulated in RGCs treated with high glucose. Overexpression of SRF significantly promoted survival among RGCs exposed to high glucose and inhibited RGC apoptosis. Knockdown of SRF exerted an inverse effect. Moreover, SRF upregulation enhanced expression of an antioxidant protein, nuclear factor erythroid 2-related factor (Nrf2), via control of the Fos-related antigen 1 (Fra-1). SRF upregulation also affected RGC survival after high-glucose treatment. Our findings showed that overexpression of SRF promoted survival of RGCs after high-glucose injury by regulating Fra-1 and Nrf2.


SRF Overexpression High glucose Fra-1 Nrf2 



Serum response factor


Retinal ganglion cell


Nuclear factor erythroid 2-related factor


Fos-related antigen 1


Diabetic retinopathy


Phosphate-buffered saline


Small-interfering RNA


3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide


  1. Aline G, Sotiropoulos A (2012) Srf: a key factor controlling skeletal muscle hypertrophy by enhancing the recruitment of muscle stem cells. Bioarchitecture 2:88–90CrossRefPubMedPubMedCentralGoogle Scholar
  2. Baarlink C, Wang H, Grosse R (2013) Nuclear actin network assembly by formins regulates the SRF coactivator MAL. Science 340:864–867CrossRefPubMedGoogle Scholar
  3. Batchuluun B, Inoguchi T, Sonoda N et al (2014) Metformin and liraglutide ameliorate high glucose-induced oxidative stress via inhibition of PKC-NAD(P)H oxidase pathway in human aortic endothelial cells. Atherosclerosis 232:156–164CrossRefPubMedGoogle Scholar
  4. Belguise K, Milord S, Galtier F, Moquet-Torcy G, Piechaczyk M, Chalbos D (2012) The PKCtheta pathway participates in the aberrant accumulation of Fra-1 protein in invasive ER-negative breast cancer cells. Oncogene 31:4889–4897CrossRefPubMedPubMedCentralGoogle Scholar
  5. Callow AD (2006) Cardiovascular disease 2005—the global picture. Vascul Pharmacol 45:302–307CrossRefPubMedGoogle Scholar
  6. Cenik BK, Garg A, McAnally JR et al (2015) Severe myopathy in mice lacking the MEF2/SRF-dependent gene leiomodin-3. J Clin Invest 125:1569–1578CrossRefPubMedPubMedCentralGoogle Scholar
  7. Chandra J, Samali A, Orrenius S (2000) Triggering and modulation of apoptosis by oxidative stress. Free Radic Biol Med 29:323–333CrossRefPubMedGoogle Scholar
  8. Chen XL, Kunsch C (2004) Induction of cytoprotective genes through Nrf2/antioxidant response element pathway: a new therapeutic approach for the treatment of inflammatory diseases. Curr Pharm Des 10:879–891CrossRefPubMedGoogle Scholar
  9. Das A, Li Q, Laws MJ, Kaya H, Bagchi MK, Bagchi IC (2012) Estrogen-induced expression of Fos-related antigen 1 (FRA-1) regulates uterine stromal differentiation and remodeling. J Biol Chem 287:19622–19630CrossRefPubMedPubMedCentralGoogle Scholar
  10. De Bosscher K, Vanden Berghe W, Haegeman G (2001) Glucocorticoid repression of AP-1 is not mediated by competition for nuclear coactivators. Mol Endocrinol 15:219–227CrossRefPubMedGoogle Scholar
  11. Dhillon AS, Tulchinsky E (2015) FRA-1 as a driver of tumour heterogeneity: a nexus between oncogenes and embryonic signalling pathways in cancer. Oncogene 34:4421–4428CrossRefPubMedPubMedCentralGoogle Scholar
  12. Garrett AJ, Dunham A (1990) Variability in radioimmunoprecipitation assays of HIV. J Virol Methods 29:341–343CrossRefPubMedGoogle Scholar
  13. Grotsch B, Brachs S, Lang C et al (2014) The AP-1 transcription factor Fra1 inhibits follicular B cell differentiation into plasma cells. J Exp Med 211:2199–2212CrossRefPubMedPubMedCentralGoogle Scholar
  14. He X, Xu H, Zhao M, Wang S (2013) Serum response factor is overexpressed in esophageal squamous cell carcinoma and promotes Eca-109 cell proliferation and invasion. Oncol Lett 5:819–824PubMedPubMedCentralGoogle Scholar
  15. Higgins LG, Hayes JD (2011) The cap'n'collar transcription factor Nrf2 mediates both intrinsic resistance to environmental stressors and an adaptive response elicited by chemopreventive agents that determines susceptibility to electrophilic xenobiotics. Chem Biol Interact 192:37–45CrossRefPubMedGoogle Scholar
  16. Horita HN, Simpson PA, Ostriker A et al (2011) Serum response factor regulates expression of phosphatase and tensin homolog through a microRNA network in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 31:2909–2919CrossRefPubMedPubMedCentralGoogle Scholar
  17. Isenmann S, Kretz A, Cellerino A (2003) Molecular determinants of retinal ganglion cell development, survival, and regeneration. Prog Retin Eye Res 22:483–543CrossRefPubMedGoogle Scholar
  18. Joung H, Kwon JS, Kim JR et al (2012) Enhancer of polycomb1 lessens neointima formation by potentiation of myocardin-induced smooth muscle differentiation. Atherosclerosis 222:84–91CrossRefPubMedGoogle Scholar
  19. Jung KI, Kim JH, Park HY, Park CK (2013) Neuroprotective effects of cilostazol on retinal ganglion cell damage in diabetic rats. J Pharmacol Exp Ther 345:457–463CrossRefPubMedGoogle Scholar
  20. Kempen JH, O'Colmain BJ, Leske MC et al (2004) The prevalence of diabetic retinopathy among adults in the United States. Arch Ophthalmol 122:552–563CrossRefPubMedGoogle Scholar
  21. Khan T, Bertram MY, Jina R, Mash B, Levitt N, Hofman K (2013) Preventing diabetes blindness: cost effectiveness of a screening programme using digital non-mydriatic fundus photography for diabetic retinopathy in a primary health care setting in South Africa. Diabetes Res Clin Pract 101:170–176CrossRefPubMedGoogle Scholar
  22. Klein BE (2007) Overview of epidemiologic studies of diabetic retinopathy. Ophthalmic Epidemiol 14:179–183CrossRefPubMedGoogle Scholar
  23. Kobayashi M, Yamamoto M (2005) Molecular mechanisms activating the Nrf2-Keap1 pathway of antioxidant gene regulation. Antioxid Redox Signal 7:385–394CrossRefPubMedGoogle Scholar
  24. Kumar V, Fahey PG, Jong YJ, Ramanan N, O'Malley KL (2012) Activation of intracellular metabotropic glutamate receptor 5 in striatal neurons leads to up-regulation of genes associated with sustained synaptic transmission including Arc/Arg3.1 protein. J Biol Chem 287:5412–5425CrossRefPubMedPubMedCentralGoogle Scholar
  25. Long X, Cowan SL, Miano JM (2013) Mitogen-activated protein kinase 14 is a novel negative regulatory switch for the vascular smooth muscle cell contractile gene program. Arterioscler Thromb Vasc Biol 33:378–386CrossRefPubMedGoogle Scholar
  26. Lu D, Chen S, Tan X et al (2012) Fra-1 promotes breast cancer chemosensitivity by driving cancer stem cells from dormancy. Cancer Res 72:3451–3456CrossRefPubMedGoogle Scholar
  27. Maggiolini M, Vivacqua A, Fasanella G et al (2004) The G protein-coupled receptor GPR30 mediates c-fos up-regulation by 17beta-estradiol and phytoestrogens in breast cancer cells. J Biol Chem 279:27008–27016CrossRefPubMedGoogle Scholar
  28. Meyer M, Schreck R, Baeuerle PA (1993) H2O2 and antioxidants have opposite effects on activation of NF-kappa B and AP-1 in intact cells: AP-1 as secondary antioxidant-responsive factor. EMBO J 12:2005–2015PubMedPubMedCentralGoogle Scholar
  29. Moquet-Torcy G, Tolza C, Piechaczyk M, Jariel-Encontre I (2014) Transcriptional complexity and roles of Fra-1/AP-1 at the uPA/Plau locus in aggressive breast cancer. Nucleic Acids Res 42:11011–11024CrossRefPubMedPubMedCentralGoogle Scholar
  30. Motrich RD, Castro GM, Caputto BL (2013) Old players with a newly defined function: Fra-1 and c-Fos support growth of human malignant breast tumors by activating membrane biogenesis at the cytoplasm. PLoS One 8:e53211CrossRefPubMedPubMedCentralGoogle Scholar
  31. Nam YJ, Song K, Luo X et al (2013) Reprogramming of human fibroblasts toward a cardiac fate. Proc Natl Acad Sci U S A 110:5588–5593CrossRefPubMedPubMedCentralGoogle Scholar
  32. Porta M, Maldari P, Mazzaglia F (2011) New approaches to the treatment of diabetic retinopathy. Diabetes Obes Metab 13:784–790CrossRefPubMedGoogle Scholar
  33. Quagliaro L, Piconi L, Assaloni R, Martinelli L, Motz E, Ceriello A (2003) Intermittent high glucose enhances apoptosis related to oxidative stress in human umbilical vein endothelial cells: the role of protein kinase C and NAD(P)H-oxidase activation. Diabetes 52:2795–2804CrossRefPubMedGoogle Scholar
  34. Rojo AI, Innamorato NG, Martin-Moreno AM, De Ceballos ML, Yamamoto M, Cuadrado A (2010) Nrf2 regulates microglial dynamics and neuroinflammation in experimental Parkinson's disease. Glia 58:588–598CrossRefPubMedGoogle Scholar
  35. Schwartz B, Marks M, Wittler L et al (2014) SRF is essential for mesodermal cell migration during elongation of the embryonic body axis. Mech Dev 133:23–35CrossRefPubMedGoogle Scholar
  36. Shibata T, Kokubu A, Gotoh M. et al. (2008) Genetic alteration of Keap1 confers constitutive Nrf2 activation and resistance to chemotherapy in gallbladder cancer. Gastroenterology 135: 1358–1368, 1368 e1351–1354Google Scholar
  37. Tkachev VO, Menshchikova EB, Zenkov NK (2011) Mechanism of the Nrf2/Keap1/ARE signaling system. Biochemistry (Mosc) 76:407–422CrossRefGoogle Scholar
  38. Vaz M, Machireddy N, Irving A et al (2012) Oxidant-induced cell death and Nrf2-dependent antioxidative response are controlled by Fra-1/AP-1. Mol Cell Biol 32:1694–1709CrossRefPubMedPubMedCentralGoogle Scholar
  39. Villeneuve NF, Lau A, Zhang DD (2010) Regulation of the Nrf2-Keap1 antioxidant response by the ubiquitin proteasome system: an insight into cullin-ring ubiquitin ligases. Antioxid Redox Signal 13:1699–1712CrossRefPubMedPubMedCentralGoogle Scholar
  40. Wiese KE, Haikala HM, von Eyss B et al. (2015) Repression of SRF target genes is critical for Myc-dependent apoptosis of epithelial cells. EMBO J e201490467Google Scholar
  41. Wong J, Zhang J, Yanagawa B et al (2012) Cleavage of serum response factor mediated by enteroviral protease 2A contributes to impaired cardiac function. Cell Res 22:360–371CrossRefPubMedPubMedCentralGoogle Scholar
  42. Yamashita K, Kim MS, Park HL et al (2008) HOP/OB1/NECC1 promoter DNA is frequently hypermethylated and involved in tumorigenic ability in esophageal squamous cell carcinoma. Mol Cancer Res 6:31–41CrossRefPubMedGoogle Scholar
  43. Yang J, Zhang Z, Chen C et al (2014) MicroRNA-19a-3p inhibits breast cancer progression and metastasis by inducing macrophage polarization through downregulated expression of Fra-1 proto-oncogene. Oncogene 33:3014–3023CrossRefPubMedGoogle Scholar
  44. Yau JW, Rogers SL, Kawasaki R et al (2012) Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care 35:556–564CrossRefPubMedPubMedCentralGoogle Scholar
  45. Yu ZW, Li D, Ling WH, Jin TR (2012) Role of nuclear factor (erythroid-derived 2)-like 2 in metabolic homeostasis and insulin action: a novel opportunity for diabetes treatment? World J Diabetes 3:19–28CrossRefPubMedPubMedCentralGoogle Scholar
  46. Zhao X, Cho H, Evans RM (2013) SRF'ing around the clock. Cell 152:381–382CrossRefPubMedGoogle Scholar
  47. Zhong G, Chen X, Fang X, Wang D, Xie M, Chen Q (2015) Fra-1 is upregulated in lung cancer tissues and inhibits the apoptosis of lung cancer cells by the P53 signaling pathway. Oncol RepGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Yan Cao
    • 1
  • Liang Wang
    • 1
  • Junhong Zhao
    • 1
  • Hongbing Zhang
    • 1
  • Ying Tian
    • 1
  • Houcheng Liang
    • 1
  • Qiang Ma
    • 1
    Email author
  1. 1.Department of OphthalmologyXi’an NO.1 HospitalXi’anChina

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