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Role of activating transcription factor 3 (ATF3) in sublytic C5b‐9‐induced glomerular mesangial cell apoptosis

Cellular & Molecular Immunology volume 7, pages 143–151 (2010)Cite this article

Abstract

Sublytic complement C5b‐9 complexes can cause cell apoptosis, but the mechanism of glomerular mesangial cell (GMC) apoptosis mediated by these complexes has not been well defined. The activating transcription factor 3 (ATF3) gene is an immediate early gene for the cell to cope with a variety of stress signals and can promote apoptosis of some cells. In this study, ATF3 expression and cell apoptosis in GMCs induced by sublytic C5b‐9 were measured, and then the effects of ATF3 gene over‐expression or knockdown on GMC apoptosis induced by sublytic C5b‐9 were examined at a fixed time. The results showed that both ATF3 expression and GMC apoptosis were markedly increased and ATF3 over‐expression obviously increased sublytic C5b‐9‐induced GMC apoptosis, whereas ATF3 gene silencing had a significant opposite effect. Collectively, these findings indicate that upregulation of ATF3 gene expression is involved in regulating GMC apoptosis induced by sublytic C5b‐9 complexes.

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References

  1. Barratt J, Feehally J, Smith AC . Pathogenesis of IgA nephropathy. Semin Nephrol 2004; 24: 197–217.

    Article  CAS  PubMed  Google Scholar 

  2. Turrnberg D, Cook HT . Complement and glomerulonephritis, new insight. Curr Opin Nephrol Hypertens 2005; 14: 223–228.

    Article  Google Scholar 

  3. Stangou M, Alexopoulos E, Pantzaki A, Leonstini M, Memmos D . C5b‐9 glomerular deposition and tubular α3β1‐integrin expression are implicated in the development of chronic lesions and predict renal function outcome in immunoglobulin A nephropathy. Scand J Urol Nephrol 2008; 42: 373–380.

    Article  CAS  PubMed  Google Scholar 

  4. Wang H, Jiang XM, Xu JH, Xu J, Tong JX, Wang YW . The profile of gene expression and role of nuclear factor kappa B on glomerular injury in rats with Thy‐1 nephritis. Clin Exp Immunol 2008; 152(3): 559–567.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ishizaki M . The presence of Thy1.1 antigen in rat glomerular mesangial cells. Allergy 1980; 29: 816–819.

    Google Scholar 

  6. Brandt J, Pippin J, Schulze M, Hänsch GM, Alpers CE, Johnson RJ, et al. Role of the complement membrane attack complex (C5b‐9) in mediating experimental mesangiopreoliferative glomerulonephritis. Kidney Int 1996; 49: 335–343.

    Article  CAS  PubMed  Google Scholar 

  7. Wang Y, He Q, Qin H, Xu J, Tong J, Gao L . The complement C5b‐9 complexes induced injury of glomerular mesangial cells in rats with Thy‐1 nephritis by increasing nitric oxide synthesis. Life Sci 2006; 79: 182–192.

    Article  CAS  PubMed  Google Scholar 

  8. Niculecu F, Rus H . Mechanisms of signal transduction activated by sublytic assembly of terminal complement complexes on nucleated cells. Immunol Res 2001; 24: 191–195.

    Article  Google Scholar 

  9. Soane L, Cho HJ, Niculescu F . C5b‐9 terminal complement complex protects oligodendrocytes from death by regulating Bad through phosphatidylinositol 3‐kinase/Akt pathway. J Immunol 2001; 167: 2305–2311.

    Article  CAS  PubMed  Google Scholar 

  10. Gao LJ, Qiu W, Wang Y, Xu W, Xu J, Tong J . Sublytic complement C5b‐9 complexes induce thrombospondin‐1 production in rat glomerular mesangial cells via PI3‐k/Akt, association with activation of latent transforming growth factor‐β1. Clin Exp Immunol 2006; 144: 326–334.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Shimizu A, Masuda Y, Kitamura H, Ishizaki M, Ohashi R, Sugisaki Y, et al. Complement‐mediated killing of mesangial cells in experimental glomerulonepphritis, cell death by a combination of apoptosis and necrosis. Nephron 2000; 86: 152–160.

    Article  CAS  PubMed  Google Scholar 

  12. Xu JH, Qiu W, Wang YW, Xu J, Tong JX, Gao LJ, et al. Gene expression profile and overexpression of apoptosis‐related genes (NGFI‐B and Gadd 45γ) in early phase of Thy‐1 nephritis model. Cell Tissue Res 2006; 326: 159–168.

    Article  CAS  PubMed  Google Scholar 

  13. Qiu W, Che N, Feng X, Xia M, Wang H, Zhao D, et al. Apoptosis of glomerular mesangial cells induced by sublytic C5b‐9 complexes in rats with Thy‐1 nephritis is dependent on Gadd45γ upregulation. Eur J Immunol 2009; 39: 3251–3266.

    Article  CAS  PubMed  Google Scholar 

  14. Liang G, Wolfgang CD, Chen BP, Chen TH, Hai T . ATF3 gene. Genomic organization, promoter, and regulation. J Biol Chem 1996; 271: 1695–1701.

    Article  CAS  PubMed  Google Scholar 

  15. Li D, Yin X, Zmuda EJ, Wolford CC, Dong X, White MF, et al. The repression of IRS2 gene by ATF3, a stress‐inducible gene, contributes to pancreatic beta‐cell apoptosis. Diabetes 2008; 57: 635–644.

    Article  CAS  PubMed  Google Scholar 

  16. Yoshida T, Sugiura H, Mitobe M, Tsuchiya K, Shirota S, Nishimura S, et al. ATF3 protects against renal ischemia‐reperfusion injury. J Am Soc Nephrol 2008; 19: 217–224.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Mei Y, Yuan Z, Song B, Li D, Ma C, Hu C, et al. Activating transcription factor 3 up‐regulated by c‐Jun NH(2)‐terminal kinase/c‐Jun contributes to apoptosis induced by potassium deprivation in cerebellar granule neurons. Neuroscience 2008; 151: 771–779.

    Article  CAS  PubMed  Google Scholar 

  18. Robey RB, Hay N . Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and Akt. Oncogene 2006; 25: 4683–4696.

    Article  CAS  PubMed  Google Scholar 

  19. Downward J . Cell biology: metabolism meets death. Nature 2003; 424: 896–897.

    Article  CAS  PubMed  Google Scholar 

  20. Couser WG, Pippin JW, Shankland SJ . Complement (C5b‐9) induces DNA synthesis in rat GMCs in vitro. Kidney Int 2001; 59: 905–912.

    Article  CAS  PubMed  Google Scholar 

  21. Gao L, Zhang Y, Qiu W, Xu W, Feng X, Ren J, et al. Effects of PI3‐k/Akt short hairpin RNA on proliferation, fibronectin production and synthesis of thrombospondin‐1 and transforming growth factor‐beta1 in glomerular mesangial cells induced by sublytic C5b‐9 complexes. Cell Prolif 2009; 42: 83–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Darvill AM, Ballardie FW . Mesangial autoantigens in IgA nephropathy: matrix synthesis and localization. J Lab Clin Med 2006; 147: 301–309.

    Article  CAS  PubMed  Google Scholar 

  23. Yamamoto T, Wilson CB . Complement dependence of antibody‐induced mesangial cell injury in the rat. J Immunol 1987; 138: 3758–3765.

    CAS  PubMed  Google Scholar 

  24. Bohana‐Kashtan O, Ziporen L, Donin N, Kraus S, Fishelson Z . Cell signals transduced by complement. Mol Immunol 2004; 41: 583–597.

    Article  PubMed  Google Scholar 

  25. Fan F, Jin S, Amundson SA, Tong T, Fan W, Zhao H, et al. ATF3 induction following DNA damage is regulated by distinct signaling pathways and over‐expression of ATF3 protein suppresses cells growth. Oncogene 2002; 21: 7488–7496.

    Article  CAS  PubMed  Google Scholar 

  26. Hartman MG, Lu D, Kim ML, Kociba GJ, Shukri T, Buteau J, et al. Role for activating transcription factor 3 in stress‐induced beta‐cell apoptosis. Mol Cell Biol 2004; 24: 5721–5732.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Huang X, Li X, Guo B . KLF6 induces apoptosis in prostate cancer cells through up‐regulation of ATF3. J Biol Chem 2008; 283: 29795–29801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Yin X, Dewille JW, Hai T . A potential dichotomous role of ATF3, an adaptive‐response gene, in cancer development. Oncogene 2008; 27: 2118–2127.

    Article  CAS  PubMed  Google Scholar 

  29. Jiang HY, Wek SA, McGrath BC, Lu D, Hai T, Harding HP, et al. Activating transcription factor 3 is integral to the eukaryotic initiation factor 2 kinase stress response. Mol Cell Biol 2004; 24: 1365–1377.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. James CG, Woods A, Underhill TM, Beier F . The transcription factor ATF3 is upregulated during chondrocyte differentiation and represses cyclin D1 and A gene transcription. BMC Mol Biol 2006; 378: 53–62.

    Google Scholar 

  31. Chen SC, Liu YC, Shyu KG, Wang DL . Acute hypoxia to endothelial cells induces activating transcription factor 3 (ATF3) expression that is mediated via nitric oxide. Atherosclerosis 2008; 201: 281–288.

    Article  CAS  PubMed  Google Scholar 

  32. Mungrue IN, Pagnon J, Kohannim O, Gargalovic PS, Lusis AJ . CHAC1/MGC4504 is a novel proapoptotic component of the unfolded protein response, downstream of the ATF4‐ATF3‐CHOP cascade. J Immunol 2009; 182: 466–476.

    Article  CAS  PubMed  Google Scholar 

  33. Niculescu F, Rus H . The role of complement activation in atherosclerosis. Immunol Res 2004; 30: 73–80.

    Article  CAS  PubMed  Google Scholar 

  34. Fosbrink M, Niculescu F, Rus H . The role of C5b‐9 terminal complement complex in activation of the cell cycle and transcription. Immunol Res 2005; 31: 37–46.

    Article  CAS  PubMed  Google Scholar 

  35. Lu D, Chen J, Hai T . The regulation of ATF3 gene expression by mitogen‐ activated protein kinase. Biochem J 2007; 401: 559–567.

    Article  CAS  PubMed  Google Scholar 

  36. Turchi L, Fareh M, Aberdam E, Kitajima S, Simpson F, Wicking C, et al. ATF3 and p15PAF are novel gatekeepers of genomic integrity upon UV stress. Cell Death Differ 2009; 16: 728–737.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Dr Jianmin Li (Nanjing Medical University, Nanjing, China) for providing the pcDNA3.1 plasmid. This work was supported by grants from the National Natural Science Foundations of China (No. 30772016), the Ministry of Education of China (No. 20060312005), and Jiangsu Provincial Department of Education (No. KJB310004) as well as Nanjing Medical University (No. 08NMUZ002 and No. 09JC007).

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  1. Professor YW Wang, Department of Microbiology and Immunology, Nanjing Medical University, 140 Nanjing Hanzhong Road, Nanjing 210029, China. E-mail: wangyw1508@njmu.edu.cn

Authors and Affiliations

  1. Department of Microbiology and Immunology, Nanjing Medical University, Nanjing, China

    Xiaoming Jiang, Jing Zhang, Mei Xia, Wen Qiu, Hui Wang, Dan Zhao & Yingwei Wang

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Jiang, X., Zhang, J., Xia, M. et al. Role of activating transcription factor 3 (ATF3) in sublytic C5b‐9‐induced glomerular mesangial cell apoptosis. Cell Mol Immunol 7, 143–151 (2010). https://doi.org/10.1038/cmi.2009.109

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