Expression of vascular endothelial growth inhibitor in diabetic retinopathy rats_Chinese Journal of Ocular Fundus Diseases

Authors：

ChenQingzhong , JiangFeng , MaoChunjie ,  颜华

Department of Ophthalmology, General Hospital of Tianjin Medical University, Tianjin 300052, China;

Corresponding author：

颜华, Email: phuayan2000@163.com

Keywords：

Diabetic retinopathy/pathophysiology; Vascular endothelial growth factors; Tumor necrosis factor-alpha

DOI：

10.3760/cma.j.issn.1005-1015.2014.02.015

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Objective To observe the expression of vascular endothelial growth inhibitor (VEGI, TL1A), vascular endothelial growth factor (VEGF), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in diabetes rats' serum, vitreous and retina, and discuss the role of VEGI in the pathogenesis of diabetic retinopathy (DR). Methods A total of p70 adult male Wistar rats were randomly divided into 4 groups, the control group (10 rats), the diabetes mellitus (DM) 1 month group (20 rats), the DM 3 month group (20 rats) and the DM 6 month group (20 rats). Cytokines of serum and vitreous were determined by enzyme-linked immunosorbent assay (ELISA), and the concentrations of the cytokines in the retina were determined by immunohistochemistry on paraffin retinal sections. Hematoxylin-eosin (HE) staining of retina was used to estimate the pathological change of DR. The results were analyzed by one-way analysis of variances, independent samples t-test and LSD test. Results The serum TL1A levels of the control group, the DM 1 month group, the DM 3 month group and the DM 6 month group rats were (92.09±2.05), (118.36±8.30), (85.90±7.51) and (78.90±4.88) ng/L respectively, the level of TL1A in serum of the DM 1 month group, the DM 3 month group and the DM 6 month group were significantly lower than that of the control group (F=77.405, P < 0.05). The concentration of serum TNF-α and IL-1β increased after DM model was established (F=3.508, 15.416; P < 0.05); the VEGF level in serum showed no difference between the groups (F=1.242, P > 0.05). The vitreous TL1A levels of the control group, the DM 1 month group, the DM 3 month group and the DM 6 month group were (91.50±8.18), (67.03±6.74), (47.44±4.92) and (46.01±4.62) ng/L respectively, every DM groups showed significant difference with the control group (F=114.777, P < 0.05); VEGF level in vitreous increased from 1 month after DM model was established (F=8.816, P < 0.05); TNF-α and IL-1β level in vitreous also showed an upward tendency (F=4.392, 3.635; P < 0.05). Paraffin section immunohistochemistry showed that the absorbance (also called optical density) of TL1A of the DM 1 month group and the DM 3 month group were significantly lower than that of the control group (t=6.851, 6.066; P < 0.05), but the DM 6 month group showed no difference with the control group (t=1.401, P > 0.05); the level of VEGF and TNF-α in DM groups were higher than that of the control group (t_VEGF=-4.709, -16.406, -9.228; t_TNF-α=-4.703, -6.583, -17.762; P < 0.05); the level of IL-1β were significantly higher in the DM 1 month group and the DM 6 month group (t=-4.108, -3.495; P > 0.05); but the DM 3 month showed no difference with the control group (t=-0.997, P > 0.05). HE staining of retina showed that the retina of the control group and the DM 1 month group had normal retinal structures, the DM 3 month group had retinal edema and disorganization, the DM 6 month group had severe retinal edema, deep stain of ganglion cells, and more neovascularization in inner plexiform layer. Conclusion VEGI is involved in the pathogenesis of DR, and it might interacts with VEGF, TNF-α and IL-1β to affect the development of DR.

Citation： ChenQingzhong, JiangFeng, MaoChunjie. Expression of vascular endothelial growth inhibitor in diabetic retinopathy rats. Chinese Journal of Ocular Fundus Diseases, 2014, 30(2): 180-186. doi: 10.3760/cma.j.issn.1005-1015.2014.02.015 Copy

1.	Stefanini FR, Arevalo JF, Maia M. Bevacizumab for the management of diabetic macular edema[J].World J Diabetes, 2013, 4:19-26.
2.	Gupta N, Mansoor S, Sharma A, et al. Diabetic retinopathy and VEGF[J]. Open Ophthalmol J, 2013, 7:4-10.
3.	Ho AC, Scott IU, Kim SJ, et al. Anti-vascular endothelial growth factor pharmacotherapy for diabetic macular edema:a report by the American Academy of Ophthalmology[J]. Ophthalmology, 2012, 119:2179-2188.
4.	Sethi G, Sung B, Aggarwal BB. Therapeutic potential of VEGI/TL1A in autoimmunity and cancer[J]. Adv Exp Med Biol, 2009, 647:207-215.
5.	Migone TS, Zhang J, Luo X, et al. TL1A is a TNF-like ligand for DR3 and TR6/DcR3 and functions as a T cell costimulator[J]. Immunity, 2002, 16:479-492.
6.	陈庆中, 张静楷, 黄利明, 等.血管内皮生长抑制因子在糖尿病视网膜病变患者血清及玻璃体中的变化[J].中华实验眼科杂志, 2013, 31:1163-1168.
7.	焦明菲, 颜华.糖尿病视网膜病变对大鼠循环外周血内皮祖细胞数量的影响[J].中华眼底病杂志, 2011, 27:250-254.
8.	Jiang RQ, Tan ZM, Deng Lei, et al. Interleukin-22 promotes human hepatocellular carcinoma by activation of STAT3[J]. Hepatology, 2011, 54, 3:900-909.
9.	Kaul K, Hodgkinson A, Tarr JM, et al. Is inflammation a common retinal-renal-nerve pathogenic link in diabetes?[J]. Curr Diabetes Rev, 2010, 6:294-303.
10.	Zeng HY, Green WR, Tso MO.Microglial activation in human diabetic retinopathy[J]. Arch Ophthalmol, 2008, 126:227-232.
11.	Wilkinson-Berka JL, Tan G, Jaworski K, et al. Identification of a retinal aldosterone system and the protective effects of mineralocorticoid receptor antagonism on retinal vascular pathology[J]. Circ Res, 2009, 104:124-133.
12.	Joussen AM, Poulaki V, Mitsiades N, et al. Nonsteroidal anti-inflammatory drugs prevent early diabetic retinopathy via TNF-α suppression[J]. FASEB J, 2002, 16:438-440.
13.	Koleva-Georgieva DN, Sivkova NP, Terzieva D. Serum inflammatory cytokines IL-1β, IL-6, TNF-α and VEGF have influence on the development of diabetic retinopathy[J]. Folia Med (Plovdiv), 2011, 53:44-50.
14.	Burgos R, Simó R, Audí L, et al. Vitreous levels of vascular endothelial growth factor are not influenced by its serum concentrations in diabetic retinopathy[J]. Diabetologia, 1997, 40:1107-1109.
15.	Meleth AD, Agrón E, Chan CC, et al. Serum inflammatory markers in diabetic retinopathy[J]. Invest Ophthalmol Vis Sci, 2005, 46:4295-4301.
16.	Suzuki Y, Nakazawa M, Suzuki K, et al. Expression profiles of cytokines and chemokines in vitreous fluid in diabetic retinopathy and central retinal vein occlusion[J]. Jpn J Ophthalmol, 2011, 55:256-263.
17.	Funatsu H, Yamashita H, Shimizu E, et al. Relationship between vascular endothelial growth factor and interleukin-6 in diabetic retinopathy[J]. Retina, 2001, 21:469-477.
18.	Murugeswari P, Shukla D, Rajendran A, et al. Proinflammatory cytokines and angiogenic and anti-angiogenic factors in vitreous of patients with proliferative diabetic retinopathy and Eales' disease[J]. Retina, 2008, 28:817-824.
19.	Wen L, Zhuang L, Luo X, et al. TL1A-induced NF-κB activation and c-IAP2 production prevent DR3-mediated apoptosis in TF-1 cells[J]. J Biol Chem, 2003, 278:39251-39258.
20.	Yu J, Tian S, Metheny-Barlow L, et al. Modulation of endothelial cell growth arrest and apoptosis by vascular endothelial growth inhibitor[J]. Circ Rec, 2001, 89:1161-1167.
21.	Haridas V, Shrivastava A, Su J, et al. VEGI, a new member of the TNF family activates nuclear factor-κB and c-Jun N-terminal kinase and modulates cell growth[J]. Oncogene, 1999, 18:6496-6504.
22.	Yue TL, Ni J, Romanic AM, et al. TL1, a novel tumor necrosis factor-like cytokine, induces apoptosis in endothelial cells. Involvement of activation of stress protein kinases (stress-activated protein kinase and p38 mitogen-activated protein kinase) and caspase-3-like protease[J]. J Biol Chem, 1999, 274:1479-1486.
23.	Bikfalvi A. Recent developments in the inhibition of angiogenesis:examples from studies on platelet factor-4 and the VEGF/VEGFR system[J]. Biochem Pharmacol, 2004, 68:1017-1021.
24.	Kim S, Zhang L. Identification of naturally secreted soluble form of TL1A, a TNF-like cytokine[J]. J Immunol Methods, 2005, 298:1-8.

1. Stefanini FR, Arevalo JF, Maia M. Bevacizumab for the management of diabetic macular edema[J].World J Diabetes, 2013, 4:19-26.
2. Gupta N, Mansoor S, Sharma A, et al. Diabetic retinopathy and VEGF[J]. Open Ophthalmol J, 2013, 7:4-10.
3. Ho AC, Scott IU, Kim SJ, et al. Anti-vascular endothelial growth factor pharmacotherapy for diabetic macular edema:a report by the American Academy of Ophthalmology[J]. Ophthalmology, 2012, 119:2179-2188.
4. Sethi G, Sung B, Aggarwal BB. Therapeutic potential of VEGI/TL1A in autoimmunity and cancer[J]. Adv Exp Med Biol, 2009, 647:207-215.
5. Migone TS, Zhang J, Luo X, et al. TL1A is a TNF-like ligand for DR3 and TR6/DcR3 and functions as a T cell costimulator[J]. Immunity, 2002, 16:479-492.
6. 陈庆中, 张静楷, 黄利明, 等.血管内皮生长抑制因子在糖尿病视网膜病变患者血清及玻璃体中的变化[J].中华实验眼科杂志, 2013, 31:1163-1168.
7. 焦明菲, 颜华.糖尿病视网膜病变对大鼠循环外周血内皮祖细胞数量的影响[J].中华眼底病杂志, 2011, 27:250-254.
8. Jiang RQ, Tan ZM, Deng Lei, et al. Interleukin-22 promotes human hepatocellular carcinoma by activation of STAT3[J]. Hepatology, 2011, 54, 3:900-909.
9. Kaul K, Hodgkinson A, Tarr JM, et al. Is inflammation a common retinal-renal-nerve pathogenic link in diabetes?[J]. Curr Diabetes Rev, 2010, 6:294-303.
10. Zeng HY, Green WR, Tso MO.Microglial activation in human diabetic retinopathy[J]. Arch Ophthalmol, 2008, 126:227-232.
11. Wilkinson-Berka JL, Tan G, Jaworski K, et al. Identification of a retinal aldosterone system and the protective effects of mineralocorticoid receptor antagonism on retinal vascular pathology[J]. Circ Res, 2009, 104:124-133.
12. Joussen AM, Poulaki V, Mitsiades N, et al. Nonsteroidal anti-inflammatory drugs prevent early diabetic retinopathy via TNF-α suppression[J]. FASEB J, 2002, 16:438-440.
13. Koleva-Georgieva DN, Sivkova NP, Terzieva D. Serum inflammatory cytokines IL-1β, IL-6, TNF-α and VEGF have influence on the development of diabetic retinopathy[J]. Folia Med (Plovdiv), 2011, 53:44-50.
14. Burgos R, Simó R, Audí L, et al. Vitreous levels of vascular endothelial growth factor are not influenced by its serum concentrations in diabetic retinopathy[J]. Diabetologia, 1997, 40:1107-1109.
15. Meleth AD, Agrón E, Chan CC, et al. Serum inflammatory markers in diabetic retinopathy[J]. Invest Ophthalmol Vis Sci, 2005, 46:4295-4301.
16. Suzuki Y, Nakazawa M, Suzuki K, et al. Expression profiles of cytokines and chemokines in vitreous fluid in diabetic retinopathy and central retinal vein occlusion[J]. Jpn J Ophthalmol, 2011, 55:256-263.
17. Funatsu H, Yamashita H, Shimizu E, et al. Relationship between vascular endothelial growth factor and interleukin-6 in diabetic retinopathy[J]. Retina, 2001, 21:469-477.
18. Murugeswari P, Shukla D, Rajendran A, et al. Proinflammatory cytokines and angiogenic and anti-angiogenic factors in vitreous of patients with proliferative diabetic retinopathy and Eales' disease[J]. Retina, 2008, 28:817-824.
19. Wen L, Zhuang L, Luo X, et al. TL1A-induced NF-κB activation and c-IAP2 production prevent DR3-mediated apoptosis in TF-1 cells[J]. J Biol Chem, 2003, 278:39251-39258.
20. Yu J, Tian S, Metheny-Barlow L, et al. Modulation of endothelial cell growth arrest and apoptosis by vascular endothelial growth inhibitor[J]. Circ Rec, 2001, 89:1161-1167.
21. Haridas V, Shrivastava A, Su J, et al. VEGI, a new member of the TNF family activates nuclear factor-κB and c-Jun N-terminal kinase and modulates cell growth[J]. Oncogene, 1999, 18:6496-6504.
22. Yue TL, Ni J, Romanic AM, et al. TL1, a novel tumor necrosis factor-like cytokine, induces apoptosis in endothelial cells. Involvement of activation of stress protein kinases (stress-activated protein kinase and p38 mitogen-activated protein kinase) and caspase-3-like protease[J]. J Biol Chem, 1999, 274:1479-1486.
23. Bikfalvi A. Recent developments in the inhibition of angiogenesis:examples from studies on platelet factor-4 and the VEGF/VEGFR system[J]. Biochem Pharmacol, 2004, 68:1017-1021.
24. Kim S, Zhang L. Identification of naturally secreted soluble form of TL1A, a TNF-like cytokine[J]. J Immunol Methods, 2005, 298:1-8.

Chinese Journal of Ocular Fundus Diseases

Expression of vascular endothelial growth inhibitor in diabetic retinopathy rats

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