The roles of Niacin in the treatment of diabetic retinopathy and its mechanism_Chinese Journal of Ocular Fundus Diseases

Authors：

WangYang ,  YanHua

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

Corresponding author：

YanHua, Email: phuayan2000@163.com

Keywords：

Blood-retinal barrier/drug effects; Niacin/agonists; Animal experimentation

DOI：

10.3760/cma.j.issn.1005-1015.2016.02.010

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Objective To investigate the protective effect of Niacin on blood-retina barrier (BRB) in diabetic rats and related mechanism. Methods The male Wistar rats (60) were divided into control (CON) group, diabetes (DM) group and Niacin-treated (NA) group, 20 rats in each group. Rats diabetes models were induced with streptozotocin injection. Niacin (40 mg/kg·d) was administrated orally everyday in Niacin-treated group until sacrificed after 3 months. Pathological outcomes, total cholesterol (TC) and high-density lipoprotein (HDL) were evaluated at month 3. Optical microscopy was used to observe the retinal structure. The integrity of BRB and the vascular permeability was quantified by analyzing albumin leakage using Evans blue (EB) method. The relative expressions of Claudin-5, Occludin, zonula occluden (ZO)-1 and GPR109A mRNA in rat retinas were detected by reverse transcription PCR (RT-PCR) and relative expression of GPR109A, tumor necrosis factor (TNF)-α and interleukin (IL)-6 by Western blot. Results Compared to CON group, the TC content was increased and HDL content was decreased in DM group (t=4.034, 5.831; P < 0.05). Compared to DM group, the TC content was decreased and HDL content was increased in NA group (t=6.868, 3.369; P < 0.05). The retinal structure of CON group was normal. Pathological changes were found in the DM group, such as tumescent nuclei and disorganized structures. The retinal structure of NA group was similar to the control group. Evans blue dye that the microvascular leakage in DM group was increased compared with CON group (t=24.712, P < 0.05), while in NA group was decreased compared with DM group (t=16.414, P < 0.05). The mRNA expression of Occludin, Claudin-5, ZO-1 in DM group were decreased compared with CON group (t=11.422, 12.638, 12.060; P < 0.05), while in NA group were increased compared with DM group (t=5.278, 3.952, 8.030; P < 0.05). The mRNA expression of GPR109A in NA group were increased compared with DM group (t=5.053, P < 0.05). The protein expression of GPR109A, IL-6, TNF-αin DM group were increased compared with CON group (t=4.915, 11.106, 6.582; P < 0.05). Compared to DM group, the protein expression of GPR109A was increased (t=5.806, P < 0.05), while the protein expression of IL-6 and TNF-α were decreased (t=10.131, 5.017; P < 0.05). Conclusion Niacin has the protective effect for BRB by up-regulating GPR109A expression which may suppress inflammation.

Citation： WangYang, YanHua. The roles of Niacin in the treatment of diabetic retinopathy and its mechanism. Chinese Journal of Ocular Fundus Diseases, 2016, 32(2): 154-158. doi: 10.3760/cma.j.issn.1005-1015.2016.02.010 Copy

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2.	Zhang W, Liu H, Al-Shabrawey M, et al. Inflammation and diabetic retinal microvascular complications [J]. J Cardiovasc Dis Res, 2011, 2(2): 96-103. DOI: 10.4103/0975-3583.83035.
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9.	Gambhir D, Ananth S, Veeranan-Karmegam R, et al. GPR109A as an anti-inflammatory receptor in retinal pigment epithelial cells and its relevance to diabetic retinopathy [J]. Invest Ophthalmol Vis Sci, 2012, 53(4): 2208-2217. DOI: 10.1167/iovs.11-8447.
10.	Kauffmann DJ, van Meurs JC, Mertens DA, et al. Cytokines in vitreous humor: interleukin-6 is elevated in proliferative vitreoretinopathy [J]. Invest Ophthalmol Vis Sci, 1994, 35(3): 900-906.
11.	Loeffler S, Fayard B, Weis J, et al. Interleukin-6 induces transcriptional activation of vascular endothelial growth factor (VEGF) in astrocytes in vivo and regulates VEGF promoter activity in glioblastoma cells via direct interaction between STAT3 and Sp1 [J]. Int J Cancer, 2005, 115(2): 202-213.
12.	Joussen AM, Poulaki V, Mitsiades N, et al. Nonsteroidal anti-inflammatory drugs prevent early diabetic retinopathy via TNF-alpha suppression [J]. FASEB J, 2002, 16(3): 438-440.
13.	Ben-Mahmud BM, Mann GE, Datti A, et al. Tumor necrosis factor-alpha in diabetic plasma increases the activity of core 2 GlcNAc-T and adherence of human leukocytes to retinal endothelial cells: significance of core 2 GlcNAc-T in diabetic retinopathy [J]. Diabetes, 2004, 53(11): 2968-2976.
14.	Aveleira CA, Lin CM, Abcouwer SF, et al. TNF-alpha signals through PKCzeta/NF-kappaB to alter the tight junction complex and increase retinal endothelial cell permeability [J]. Diabetes, 2010, 59(11): 2872-2882. DOI: 10.2337/db09-1606.

1. Kim JH, Kim JH, Yu YS, et al. Blockade of angiotensin Ⅱ attenuates VEGF-mediated blood-retinal barrier breakdown in diabetic retinopathy [J]. J Cereb Blood Flow Metab, 2009, 29(3): 621-628. DOI: 10.1038/jcbfm.2008.154.
2. Zhang W, Liu H, Al-Shabrawey M, et al. Inflammation and diabetic retinal microvascular complications [J]. J Cardiovasc Dis Res, 2011, 2(2): 96-103. DOI: 10.4103/0975-3583.83035.
3. Farmer JA. Nicotinic acid: a new look at an old drug [J]. Curr Atheroscler Rep, 2009, 11(2): 87-92.
4. Martin PM, Ananth S, Cresci G, et al. Expression and localization of GPR109A (PUMA-G/HM74A) mRNA and protein in mammalian retinal pigment epithelium [J]. Mol Vis, 2009, 15:362-372.
5. Algandaby MM, Alghamdi HA, Ashour OM, et al. Mechanisms of the antihyperglycemic activity of Retama raetam in streptozotocin-induced diabetic rats [J]. Food Chem Toxicol, 2010, 48(8-9): 2448-2453. DOI: 10.1016/j.fct.2010.06.010.
6. Xu Q, Qaum T, Adamis AP. Sensitive blood-retinal barrier breakdown quantitation using Evans blue [J]. Invest Ophthalmol Vis Sci, 2001, 42(3): 789-794.
7. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method [J]. Methods, 2001, 25(4): 402-408.
8. Soga T, Kamohara M, Takasaki J, et al. Molecular identification of nicotinic acid receptor [J]. Biochem Biophys Res Commun, 2003, 303(1): 364-369.
9. Gambhir D, Ananth S, Veeranan-Karmegam R, et al. GPR109A as an anti-inflammatory receptor in retinal pigment epithelial cells and its relevance to diabetic retinopathy [J]. Invest Ophthalmol Vis Sci, 2012, 53(4): 2208-2217. DOI: 10.1167/iovs.11-8447.
10. Kauffmann DJ, van Meurs JC, Mertens DA, et al. Cytokines in vitreous humor: interleukin-6 is elevated in proliferative vitreoretinopathy [J]. Invest Ophthalmol Vis Sci, 1994, 35(3): 900-906.
11. Loeffler S, Fayard B, Weis J, et al. Interleukin-6 induces transcriptional activation of vascular endothelial growth factor (VEGF) in astrocytes in vivo and regulates VEGF promoter activity in glioblastoma cells via direct interaction between STAT3 and Sp1 [J]. Int J Cancer, 2005, 115(2): 202-213.
12. Joussen AM, Poulaki V, Mitsiades N, et al. Nonsteroidal anti-inflammatory drugs prevent early diabetic retinopathy via TNF-alpha suppression [J]. FASEB J, 2002, 16(3): 438-440.
13. Ben-Mahmud BM, Mann GE, Datti A, et al. Tumor necrosis factor-alpha in diabetic plasma increases the activity of core 2 GlcNAc-T and adherence of human leukocytes to retinal endothelial cells: significance of core 2 GlcNAc-T in diabetic retinopathy [J]. Diabetes, 2004, 53(11): 2968-2976.
14. Aveleira CA, Lin CM, Abcouwer SF, et al. TNF-alpha signals through PKCzeta/NF-kappaB to alter the tight junction complex and increase retinal endothelial cell permeability [J]. Diabetes, 2010, 59(11): 2872-2882. DOI: 10.2337/db09-1606.

Chinese Journal of Ocular Fundus Diseases

The roles of Niacin in the treatment of diabetic retinopathy and its mechanism

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