The effect of netrin-1 on the retinal vascular permeability in diabetes mellitus rats_Chinese Journal of Ocular Fundus Diseases

Authors：

Zhou Xianhui ,  Meng Xuxia , Fu Yudong , Liu Penghui , Hu Die

Department of Ophthalmology, The Affiliated of Qingdao University, Qingdao 266500, China (Zhou Xianhui, now working at the Department of Ophthalmology, Yantai YeDa Hospital; Hu Die, now working at the Qingdao Eye Hospital);

Corresponding author：

Meng Xuxia, Email: mengxuxia@163.com

Keywords：

Diabetic retinopathy/physiopathology; Blood retinal barrier/physiopathology; Nerve growth factors; Animal experimentation

DOI：

10.3760/cma.j.issn.1005-1015.2017.03.015

Video：

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Objective To observe the effect of different concentration netrin-1 on retinal vascular permeability in diabetes mellitus (DM) rats. Methods Eighty adult Sprague-Dawley rats were randomly divided into 8 groups, 10 rats in each group, including normal control group (group A), normal＋balanced salt solution (BSS) group (group B), normal＋netrin-1 (500 μg/ml) group (group C) and DM group (50 rats in 5 sub-groups). DM rats were induced by intraperitoneal injection of streptozocin. Three months after intraperitoneal injection, 10 DM rats in the control group were injected with BSS (group D). Forty DM rats were injected with 5 μl of different concentrate netrin-1, and were divided into DM+netrin-1 10 μg/ml group (group E), DM+netrin-1 50 μg/ml group (group F), DM＋netrin-1 100 μg/ml group (group G), DM＋netrin-1 500 μg/ml group (group H) according to the different concentration. Non-DM rats in group C were injected with netrin-1 500 μg/ml. The expression of occludin was determined by immunohistochemistry for protein, and by real-time fluorescence quantitative reverse transcription polymerase chain reaction for mRNA level. Retinal vascular permeability was measured by Evans blue infusion. Results The expression of occludin protein and mRNA in group D were less than group A (t=27.71, 8.59;P=0.00, 0.00). However, the retinal vascular permeability increased in group D (t=−42.72,P=0.00). The expression of occluding protein, occludin mRNA and retinal vascular permeability showed significant differences between group D, E, F, G and H (F=146.31, 16.54, 67.77;P=0.00, 0.00, 0.00). Compared the group B with group C, there was no significant differences between the expression of occludin protein, occludin mRNA and the retinal vascular permeability (t=−1.13, 0.93, 1.04;P=0.27, 0.36, 0.31). The concentrate of netrin-1 showed a significant positive correlation to the expression level of occludin and occludin mRNA (r=0.73, 0.81;P=0.00, 0.00), but negative correlation to the vascular permeability (r=−0.61,P=0.00). Conclusion Netrin-1 can reduce the DM rats' retinal vascular permeability, which depended on the concentration of netrin-1.

Citation： Zhou Xianhui, Meng Xuxia, Fu Yudong, Liu Penghui, Hu Die. The effect of netrin-1 on the retinal vascular permeability in diabetes mellitus rats. Chinese Journal of Ocular Fundus Diseases, 2017, 33(3): 286-289. doi: 10.3760/cma.j.issn.1005-1015.2017.03.015 Copy

1.	Lennikov A, Hiraoka M, Abe A, et al. IκB kinase-β inhibitor IMD-0354 beneficially suppresses retinal vascular permeability in streptozotocin-induced diabetic mice[J]. Invest Ophthalmol Vis Sci, 2014, 55(10): 6365-6373. DOI: 10.1167/iovs.14-14671.
2.	Roy S, Kim D, Hemandez C, et al. Beneficial effects of fenofibric acid on overexpression of extracellular matrix components, COX-2, and impairment of endothelial permeability associated with diabetic retinopathy[J]. Exp Eye Res, 2015, 140: 124-129. DOI: 10.1016/j.exer.2015.08.010.
3.	周贤慧, 孟旭霞, 孙运波, 等. 轴突导向因子netrin-1对早期糖尿病大鼠血视网膜屏障的影响[J]. 中华眼底病杂志, 2015, 31(5): 472-476. DOI: 10.3760/cma.j.issn.1005-1015.2015.05.015.Zhou XH, Meng XX, Sun YB, et al. The effect of netrin-1 on the retinal vascular permeability in early diabetic retinopathy rats[J] Chin J Ocul Fundus Dis, 2015, 31(5): 472-476. DOI: 10.3760/cma.j.issn.1005-1015.2015.05.015.
4.	Yu Y, Zou J, Han Y, et al. Effects of intravitreal injection of netrin-1 in retinal neovascularization of streptozotocin-induced diabetic rats[J]. Drug Des Devel Ther, 2015, 9: 6363-6377. DOI: 10.2147/DDDT.S93166.
5.	Northrop NA, Yamamoto BK. Persistent neuroinflammatory effects of serial exposure to stress and methamphetamine on the blood-brain barrier[J]. J Neuroimmune Pharmacol, 2012, 7(4): 951-968. DOI: 10.1007/s11481-012-9391-y.
6.	Gott M,Joussen AM,Klein C,et al. Role of syndecan-1 in leukocyte-endothelial interactions in the ocular vasculature[J].Invest Ophthalmol Vis Sci,2002,43(4):1135-1141.
7.	Algandaby MM, Alghamdi HA, Ashour OM, et al. Mechanisms of the antihyperglycemic activity of Retamaraetam in streptozotocin induced diabetic rats[J]. Food Chem Toxicol, 2010, 48(8-9): 2448-2453. DOI: 10.1016/j.fct.2010.06.010.
8.	Wilson BD, Ii M, Park KW, et al. Netrins promote developmental and therapeutic angiogenesis[J]. Science, 2006, 313(5787): 640-644.
9.	Xu H, Liu J, Xiong S, et al. Suppression of retinal neovascularization by lentivirus-mediated netrin-1 small hairpin RNA[J]. Ophthalmic Res, 2012, 47(3): 163-169. DOI: 10.1159/000331428.
10.	Zhang X, Liu J, Xiong S, et al. Expression of netrin-1 in diabetic rat retina[J]. Eye Sci, 2013, 28(3): 148-152.
11.	Liu J, Xia X, Xiong S, et al. Intravitreous high expression level of netrin-1 in patients with proliferative diabetic retinopathy[J]. Eye Sci, 2011, 26(2): 35-42. DOI: 10.3969/j.issn.1000-4432.2011.02.017.
12.	Tu T, Zhang C, Yan H, et al. CD146 acts as a novel receptor for netrin-1 in promoting angiogenesis and vascular development[J]. Cell Res, 2015, 25(3): 275-287. DOI: 10.1038/cr.2015.15.

1. Lennikov A, Hiraoka M, Abe A, et al. IκB kinase-β inhibitor IMD-0354 beneficially suppresses retinal vascular permeability in streptozotocin-induced diabetic mice[J]. Invest Ophthalmol Vis Sci, 2014, 55(10): 6365-6373. DOI: 10.1167/iovs.14-14671.
2. Roy S, Kim D, Hemandez C, et al. Beneficial effects of fenofibric acid on overexpression of extracellular matrix components, COX-2, and impairment of endothelial permeability associated with diabetic retinopathy[J]. Exp Eye Res, 2015, 140: 124-129. DOI: 10.1016/j.exer.2015.08.010.
3. 周贤慧, 孟旭霞, 孙运波, 等. 轴突导向因子netrin-1对早期糖尿病大鼠血视网膜屏障的影响[J]. 中华眼底病杂志, 2015, 31(5): 472-476. DOI: 10.3760/cma.j.issn.1005-1015.2015.05.015.Zhou XH, Meng XX, Sun YB, et al. The effect of netrin-1 on the retinal vascular permeability in early diabetic retinopathy rats[J] Chin J Ocul Fundus Dis, 2015, 31(5): 472-476. DOI: 10.3760/cma.j.issn.1005-1015.2015.05.015.
4. Yu Y, Zou J, Han Y, et al. Effects of intravitreal injection of netrin-1 in retinal neovascularization of streptozotocin-induced diabetic rats[J]. Drug Des Devel Ther, 2015, 9: 6363-6377. DOI: 10.2147/DDDT.S93166.
5. Northrop NA, Yamamoto BK. Persistent neuroinflammatory effects of serial exposure to stress and methamphetamine on the blood-brain barrier[J]. J Neuroimmune Pharmacol, 2012, 7(4): 951-968. DOI: 10.1007/s11481-012-9391-y.
6. Gott M,Joussen AM,Klein C,et al. Role of syndecan-1 in leukocyte-endothelial interactions in the ocular vasculature[J].Invest Ophthalmol Vis Sci,2002,43(4):1135-1141.
7. Algandaby MM, Alghamdi HA, Ashour OM, et al. Mechanisms of the antihyperglycemic activity of Retamaraetam in streptozotocin induced diabetic rats[J]. Food Chem Toxicol, 2010, 48(8-9): 2448-2453. DOI: 10.1016/j.fct.2010.06.010.
8. Wilson BD, Ii M, Park KW, et al. Netrins promote developmental and therapeutic angiogenesis[J]. Science, 2006, 313(5787): 640-644.
9. Xu H, Liu J, Xiong S, et al. Suppression of retinal neovascularization by lentivirus-mediated netrin-1 small hairpin RNA[J]. Ophthalmic Res, 2012, 47(3): 163-169. DOI: 10.1159/000331428.
10. Zhang X, Liu J, Xiong S, et al. Expression of netrin-1 in diabetic rat retina[J]. Eye Sci, 2013, 28(3): 148-152.
11. Liu J, Xia X, Xiong S, et al. Intravitreous high expression level of netrin-1 in patients with proliferative diabetic retinopathy[J]. Eye Sci, 2011, 26(2): 35-42. DOI: 10.3969/j.issn.1000-4432.2011.02.017.
12. Tu T, Zhang C, Yan H, et al. CD146 acts as a novel receptor for netrin-1 in promoting angiogenesis and vascular development[J]. Cell Res, 2015, 25(3): 275-287. DOI: 10.1038/cr.2015.15.

Chinese Journal of Ocular Fundus Diseases

The effect of netrin-1 on the retinal vascular permeability in diabetes mellitus rats

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