视紫红质类及卷曲蛋白受体在糖尿病视网膜病变发生发展中的作用_Chinese Journal of Ocular Fundus Diseases

Authors：

傅平平 ,  吴强

200233 上海交通大学医学院附属第六人民医院眼科;

Corresponding author：

吴强, Email: wyan559@hotmail.com

Keywords：

糖尿病视网膜病变/病因学; 受体, G-蛋白偶联; Frizzled受体; 综述

DOI：

10.3760/cma.j.issn.1005-1015.2014.04.030

Video：

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鸟苷酸结合蛋白偶联受体(GPCRs)是一类膜受体超家族, 被视为最好的药物靶点。在糖尿病视网膜病变(DR)进程中有大量不同亚型GPCRs参与。其中, 视紫红质类和卷曲蛋白(Frizzled)受体广受关注, 研究方向主要为视网膜炎症反应、新生血管生成、神经元和神经胶质细胞损伤等。血管紧张素Ⅱ受体是最为熟知的视紫红质类受体亚家族。应用血管紧张素Ⅱ受体1拮抗剂可显著降低1型糖尿病患者发生DR的可能性, 但无法减缓已并发DR患者的病变进展; 可减缓并发轻中度DR的2型糖尿病患者的病变进展。其他的视紫红质类受体还有趋化因子受体、大麻素相关受体、GPR91、GPR109A、APJ受体等。Frizzled受体是Wnt信号通路重要的膜受体等。在DR动物模型中, 使用Wnt通路阻断剂Dickkopf homolog 1能改善视网膜炎症、血管渗出、新生血管生成等。但Wnt通路参与DR进展的具体机制有待研究。随着对GPCRs与DR关系了解的加深, 未来将有更多以GPCRs为治疗靶点的药物应用于临床, 为DR患者带来福音。

Citation： 傅平平, 吴强. 视紫红质类及卷曲蛋白受体在糖尿病视网膜病变发生发展中的作用. Chinese Journal of Ocular Fundus Diseases, 2014, 30(4): 431-434. doi: 10.3760/cma.j.issn.1005-1015.2014.04.030 Copy

1.	Lohse MJ, Maiellaro I, Calebiro D. Kinetics and mechanism of G protein-coupled receptor activation[J]. Curr Opin Cell Biol, 2013, 27:87-93.
2.	Manglik A, Kobilka B. The role of protein dynamics in GPCR function: insights from the β₂AR and rhodopsin[J]. Curr Opin Cell Biol, 2014, 27:136-143.
3.	Dror RO, Pan AC, Arlow DH, et al. Pathway and mechanism of drug binding to G-protein-coupled receptors[J]. Proc Natl Acad Sci USA, 2011, 108:13118-13123.
4.	Lee HJ, Song IC, Yun HJ, et al. CXC chemokines and chemokine receptors in gastric cancer: from basic findings towards therapeutic targeting[J]. World J Gastroenterol, 2014, 20:1681-1693.
5.	Pierce KL, Premont RT, Lefkowitz RJ. Seven-transmembrane receptors[J]. Nat Rev Mol Cell Biol, 2002, 3:639-650.
6.	Mendelsohn FA. Localization and properties of angiotensin receptors[J]. J Hypertens, 1985, 3:307-316.
7.	Guan AL, Gong H, Ye Y, et al. Regulation of p53 by Jagged1 contributes to angiotensin Ⅱ-induced impairment of myocardial angiogenesis[J/OL]. PLoS One, 2013, 8:76529[2013-10-10]. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0076529.
8.	Du HY, Liang ZB, Zhang YL, et al. Effects of angiotensin Ⅱ type 2 receptor overexpression on the growth of hepatocellular carcinoma cells in vitro and in vivo[J/OL]. PLoS One, 2013, 8:E83754[2013-10-10]. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0083754.
9.	Gerhardinger C, Costa MB, Coulombe MC, et al. Expression of acute-phase response proteins in retinal Müller cells in diabetes[J]. Invest Ophthalmol Vis Sci, 2005, 46:349-357.
10.	Senanayake Pd, Drazba J, Shadrach K, et al. Angiotensin Ⅱ and its receptor subtypes in the human retina[J]. Invest Ophthalmol Vis Sci, 2007, 48:3301-3311.
11.	Downie LE, Vessey K, Miller A, et al. Neuronal and glial cell expression of angiotensin Ⅱ type 1(AT1) and type 2(AT2) receptors in the rat retina[J]. Neuroscience, 2009, 161:195-213.
12.	Nagai N, Izumi-Nagai K, Oike Y, et al. Suppression of diabetes-induced retinal inflammation by blocking the angiotensin Ⅱ type 1 receptor or its downstream nuclear factor-κB pathway[J]. Invest Ophthalmol Vis Sci, 2007, 48:4342-4350.
13.	Funatsu H, Yamashita H, Ikeda T, et al. Relation of diabetic macular edema to cytokines and posterior vitreous detachment[J]. Am J Ophthalmol, 2003, 135:321-327.
14.	Gao BB, Chen XH, Timothy N, et al. Characterization of the vitreous proteome in diabetes without diabetic retinopathy and diabetes with proliferative diabetic retinopathy[J]. J Proteome Res, 2008, 7:2516-2525.
15.	Zheng Z, Chen HB, Ke GJ, et al. Protective effect of perindopril on diabetic retinopathy is associated with decreased vascular endothelial growth factor-to-pigment epithelium-derived factor ratio: involvement of a mitochondria-reactive oxygen species pathway[J]. Diabetes, 2009, 58:954-964.
16.	Zheng Z, Chen H, Xu X, et al. Effects of angiotensin-converting enzyme inhibitors and beta-adrenergic blockers on retinal vascular endothelial growth factor expression in rat diabetic retinopathy[J]. Exp Eye Res, 2007, 84:745-752.
17.	Horio N, Clermont AC, Abiko A, et al. Angiotensin AT1 receptor antagonism normalizes retinal blood flow and acetylcholine-induced vasodilatation in normotensive diabetic rats[J]. Diabetologia, 2004, 47:113-123.
18.	Phipps JA, Clermont AC, Sinha S, et al. Plasma kallikrein mediates angiotensin Ⅱ type 1 receptor-stimulated retinal vascular permeability[J]. Hypertension, 2009, 53:175-181.
19.	Gilbert RE, Kelly DJ, Cox AJ, et al. Angiotensin converting enzyme inhibition reduces retinal overexpression of vascular endothelial growth factor and hyperpermeability in experimental diabetes[J]. Diabetologia, 2000, 43:1360-1367.
20.	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, 29:621-628.
21.	Chen P, Scicli GM, Guo M, et al. Role of angiotensin Ⅱ in retinal leukostasis in the diabetic rat[J]. Exp Eye Res, 2006, 83:1041-1051.
22.	Miller AG, Tan G, Binger KJ, et al. Candesartan attenuates diabetic retinal vascular pathology by restoring glyoxalase-Ⅰ function[J]. Diabetes, 2010, 59:3208-3215.
23.	Qaum T, Xu QW, Joussen AM, et al. VEGF-initiated blood-retinal barrier breakdown in early diabetes[J]. Invest Ophthalmol Vis Sci, 2001, 42:2408-2413.
24.	Bui BV, Armitage JA, Tolcos M, et al. ACE inhibition salvages the visual loss caused by diabetes[J]. Diabetologia, 2003, 46:401-408.
25.	Chaturvedi N, Porta M, Klein R, et al. Effect of candesartan on prevention (DIRECT-Prevent 1) and progression (DIRECT-Protect 1) of retinopathy in type 1 diabetes: randomised, placebo-controlled trials[J]. Lancet, 2008, 372:1394-1402.
26.	Sjølie AK, Klein R, Porta M, et al. Effect of candesartan on progression and regression of retinopathy in type 2 diabetes (DIRECT-Protect 2): a randomised placebo-controlled trial[J]. Lancet, 2008, 372:1385-1393.
27.	Balkwill FR. The chemokine system and cancer[J]. J Pathol, 2012, 226:148-157.
28.	Adamis AP. Is diabetic retinopathy an inflammatory disease?[J]. Br J Ophthalmol, 2002, 86:363-365.
29.	Dimberg A. Chemokines in angiogenesis[J]. Curr Top Microbiol Immunol, 2010, 341:59-80.
30.	Bernardini G, Ribatti D, Spinetti G, et al. Analysis of the role of chemokines in angiogenesis[J]. J Immunol Methods, 2003, 273:83-101.
31.	Murakami T, Frey T, Lin C, et al. Protein kinase Cβ phosphorylates occludin regulating tight junction trafficking in vascular endothelial growth factor-induced permeability in vivo[J]. Diabetes, 2012, 61:1573-1583.
32.	Manitiu ML. The endocannabinoid system and its role in the pathogenesis and treatment of cardiovascular disturbances in cirrhosis[J]. Acta Gastroenterol Belg, 2013, 76:195-199.
33.	Chiurchiù V, Lanuti M, Catanzaro G, et al. Detailed characterization of the endocannabinoid system in human macrophages and foam cells, and anti-inflammatory role of type-2 cannabinoid receptor[J]. Atherosclerosis, 2014, 233:55-63.
34.	Horváth B, Mukhopadhyay P, Haskó G, et al. The endocannabinoid system and plant-derived cannabinoids in diabetes and diabetic complications[J]. Am J Pathol, 2012, 180:432-442.
35.	Jenkin KA, Verty ANA, McAinch AJ, et al. Endocannabinoids and the renal proximal tubule: an emerging role in diabetic nephropathy[J]. Int J Biochem Cell Biol, 2012, 44:2028-2031.
36.	Rajesh M, Bátkai S, Kechrid M, et al. Cannabinoid 1 receptor promotes cardiac dysfunction, oxidative stress, inflammation, and fibrosis in diabetic cardiomyopathy[J]. Diabetes, 2012, 61:716-727.
37.	Buraczynska M, Wacinski P, Zukowski P, et al. Common polymorphism in the cannabinoid type 1 receptor gene (CNR1) is associated with microvascular complications in type 2 diabetes[J]. J Diabetes Complications, 2014, 28:35-39.
38.	Lim SK, Park MJ, Lim JC, et al. Hyperglycemia induces apoptosis via CB1 activation through the decrease of FAAH 1 in retina pigment epithelial cells[J]. J Cell Physiol, 2012, 227:569-577.
39.	El-Remessy AB, Rajesh M, Mukhopadhyay P, et al. Cannabinoid 1 receptor activation contributes to vascular inflammation and cell death in a mouse model of diabetic retinopathy and a human retinal cell line[J]. Diabetologia, 2011, 54:1567-1578.
40.	Sapieha P, Sirinyan M, Hamel D, et al. The succinate receptor GPR91 in neurons has a major role in retinal angiogenesis[J]. Nat Med, 2008, 14:1067-1076.
41.	Peti-Peterdi J. High glucose and renin release: the role of succinate and GPR91[J]. Kidney Int, 2010, 78:1214-1217.
42.	Toma I, Kang JJ, Sipos A, et al. Succinate receptor GPR91 provides a direct link between high glucose levels and renin release in murine and rabbit kidney[J]. J Clin Invest, 2008, 118:2526-2534.
43.	Hu JY, Wu Q, Li TT, et al. Inhibition of high glucose-induced VEGF release in retinal ganglion cells by RNA interference targeting G protein-coupled receptor 91[J]. Exp Eye Res, 2013, 109:31-39.
44.	Ariza AC, Deen PM, Robben JH. The succinate receptor as a novel therapeutic target for oxidative and metabolic stress-related conditions[J/OL]. Front Endocrinol (Lausanne), 2012, 3:22[2013-10-28]. http://journal.frontiersin.org/Journal/10.3389/fendo.2012.00022/full.
45.	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, 53:2208-2217.
46.	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.
47.	Digby JE, McNeill E, Dyar OJ, et al. Anti-inflammatory effects of nicotinic acid in adipocytes demonstrated by suppression of fractalkine, RANTES, and MCP-1 and upregulation of adiponectin[J]. Atherosclerosis, 2010, 209:89-95.
48.	Lukasova M, Malaval C, Gille A, et al. Nicotinic acid inhibits progression of atherosclerosis in mice through its receptor GPR109A expressed by immune cells[J]. J Clin Invest, 2011, 121:1163-1173.
49.	Yu XH, Tang ZB, Liu LJ, et al. Apelin and its receptor APJ in cardiovascular diseases[J]. Clin Chim Acta, 2014, 428:1-8.
50.	Kang YJ, Kim JM, Anderson JP, et al. Apelin-APJ signaling is a critical regulator of endothelial MEF2 activation in cardiovascular development[J]. Circ Res, 2013, 113:22-31.
51.	O'Carroll AM, Lolait SJ, Harris LE, et al. The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis[J]. J Endocrinol, 2013, 219:13-35.
52.	Tao Y, Lu Q, Jiang YR, et al. Apelin in plasma and vitreous and in fibrovascular retinal membranes from patients with proliferative diabetic retinopathy[J]. Invest Ophthalmol Vis Sci, 2010, 51:4237-4242.
53.	Kasai A, Ishimaru Y, Kinjo T, et al. Apelin is a crucial factor for hypoxia-induced retinal angiogenesis[J]. Arterioscler Thromb Vasc Biol, 2010, 30:2182-2187.
54.	Schulte G, Bryja V. The Frizzled family of unconventional G-protein-coupled receptors[J]. Trends Pharmacol Sci, 2007, 28:518-525.
55.	Sui L, Bouwens L, Mfopou JK. Signaling pathways during maintenance and definitive endoderm differentiation of embryonic stem cells[J]. Int J Dev Biol, 2013, 57:1-12.
56.	Kim W, Kim M, Jho EH. Wnt/β-catenin signalling: from plasma membrane to nucleus[J]. Biochem J, 2013, 450:9-21.
57.	Stewart DJ. Wnt signaling pathway in non-small cell lung cancer[J]. J Natl Cancer Inst, 2014, 106:djt356.
58.	Wang YS, Rattner A, Zhou YL, et al. Norrin/Frizzled4 signaling in retinal vascular development and blood brain barrier plasticity[J]. Cell, 2012, 151:1332-1344.
59.	Ye X, Wang YS, Cahill H, et al. Norrin, frizzled-4, and Lrp5 signaling in endothelial cells controls a genetic program for retinal vascularization[J]. Cell, 2009, 139:285-298.
60.	Nikopoulos K, Venselaar H, Collin RWJ, et al. Overview of the mutation spectrum in familial exudative vitreoretinopathy and Norrie disease with identification of 21 novel variants in FZD4, LRP5, and NDP[J]. Hum Mutat, 2010, 31:656-666.
61.	Chen Y, Hu Y, Zhou T, et al. Activation of the Wnt pathway plays a pathogenic role in diabetic retinopathy in humans and animal models[J]. Am J Pathol, 2009, 175:2676-2685.

1. Lohse MJ, Maiellaro I, Calebiro D. Kinetics and mechanism of G protein-coupled receptor activation[J]. Curr Opin Cell Biol, 2013, 27:87-93.
2. Manglik A, Kobilka B. The role of protein dynamics in GPCR function: insights from the β₂AR and rhodopsin[J]. Curr Opin Cell Biol, 2014, 27:136-143.
3. Dror RO, Pan AC, Arlow DH, et al. Pathway and mechanism of drug binding to G-protein-coupled receptors[J]. Proc Natl Acad Sci USA, 2011, 108:13118-13123.
4. Lee HJ, Song IC, Yun HJ, et al. CXC chemokines and chemokine receptors in gastric cancer: from basic findings towards therapeutic targeting[J]. World J Gastroenterol, 2014, 20:1681-1693.
5. Pierce KL, Premont RT, Lefkowitz RJ. Seven-transmembrane receptors[J]. Nat Rev Mol Cell Biol, 2002, 3:639-650.
6. Mendelsohn FA. Localization and properties of angiotensin receptors[J]. J Hypertens, 1985, 3:307-316.
7. Guan AL, Gong H, Ye Y, et al. Regulation of p53 by Jagged1 contributes to angiotensin Ⅱ-induced impairment of myocardial angiogenesis[J/OL]. PLoS One, 2013, 8:76529[2013-10-10]. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0076529.
8. Du HY, Liang ZB, Zhang YL, et al. Effects of angiotensin Ⅱ type 2 receptor overexpression on the growth of hepatocellular carcinoma cells in vitro and in vivo[J/OL]. PLoS One, 2013, 8:E83754[2013-10-10]. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0083754.
9. Gerhardinger C, Costa MB, Coulombe MC, et al. Expression of acute-phase response proteins in retinal Müller cells in diabetes[J]. Invest Ophthalmol Vis Sci, 2005, 46:349-357.
10. Senanayake Pd, Drazba J, Shadrach K, et al. Angiotensin Ⅱ and its receptor subtypes in the human retina[J]. Invest Ophthalmol Vis Sci, 2007, 48:3301-3311.
11. Downie LE, Vessey K, Miller A, et al. Neuronal and glial cell expression of angiotensin Ⅱ type 1(AT1) and type 2(AT2) receptors in the rat retina[J]. Neuroscience, 2009, 161:195-213.
12. Nagai N, Izumi-Nagai K, Oike Y, et al. Suppression of diabetes-induced retinal inflammation by blocking the angiotensin Ⅱ type 1 receptor or its downstream nuclear factor-κB pathway[J]. Invest Ophthalmol Vis Sci, 2007, 48:4342-4350.
13. Funatsu H, Yamashita H, Ikeda T, et al. Relation of diabetic macular edema to cytokines and posterior vitreous detachment[J]. Am J Ophthalmol, 2003, 135:321-327.
14. Gao BB, Chen XH, Timothy N, et al. Characterization of the vitreous proteome in diabetes without diabetic retinopathy and diabetes with proliferative diabetic retinopathy[J]. J Proteome Res, 2008, 7:2516-2525.
15. Zheng Z, Chen HB, Ke GJ, et al. Protective effect of perindopril on diabetic retinopathy is associated with decreased vascular endothelial growth factor-to-pigment epithelium-derived factor ratio: involvement of a mitochondria-reactive oxygen species pathway[J]. Diabetes, 2009, 58:954-964.
16. Zheng Z, Chen H, Xu X, et al. Effects of angiotensin-converting enzyme inhibitors and beta-adrenergic blockers on retinal vascular endothelial growth factor expression in rat diabetic retinopathy[J]. Exp Eye Res, 2007, 84:745-752.
17. Horio N, Clermont AC, Abiko A, et al. Angiotensin AT1 receptor antagonism normalizes retinal blood flow and acetylcholine-induced vasodilatation in normotensive diabetic rats[J]. Diabetologia, 2004, 47:113-123.
18. Phipps JA, Clermont AC, Sinha S, et al. Plasma kallikrein mediates angiotensin Ⅱ type 1 receptor-stimulated retinal vascular permeability[J]. Hypertension, 2009, 53:175-181.
19. Gilbert RE, Kelly DJ, Cox AJ, et al. Angiotensin converting enzyme inhibition reduces retinal overexpression of vascular endothelial growth factor and hyperpermeability in experimental diabetes[J]. Diabetologia, 2000, 43:1360-1367.
20. 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, 29:621-628.
21. Chen P, Scicli GM, Guo M, et al. Role of angiotensin Ⅱ in retinal leukostasis in the diabetic rat[J]. Exp Eye Res, 2006, 83:1041-1051.
22. Miller AG, Tan G, Binger KJ, et al. Candesartan attenuates diabetic retinal vascular pathology by restoring glyoxalase-Ⅰ function[J]. Diabetes, 2010, 59:3208-3215.
23. Qaum T, Xu QW, Joussen AM, et al. VEGF-initiated blood-retinal barrier breakdown in early diabetes[J]. Invest Ophthalmol Vis Sci, 2001, 42:2408-2413.
24. Bui BV, Armitage JA, Tolcos M, et al. ACE inhibition salvages the visual loss caused by diabetes[J]. Diabetologia, 2003, 46:401-408.
25. Chaturvedi N, Porta M, Klein R, et al. Effect of candesartan on prevention (DIRECT-Prevent 1) and progression (DIRECT-Protect 1) of retinopathy in type 1 diabetes: randomised, placebo-controlled trials[J]. Lancet, 2008, 372:1394-1402.
26. Sjølie AK, Klein R, Porta M, et al. Effect of candesartan on progression and regression of retinopathy in type 2 diabetes (DIRECT-Protect 2): a randomised placebo-controlled trial[J]. Lancet, 2008, 372:1385-1393.
27. Balkwill FR. The chemokine system and cancer[J]. J Pathol, 2012, 226:148-157.
28. Adamis AP. Is diabetic retinopathy an inflammatory disease?[J]. Br J Ophthalmol, 2002, 86:363-365.
29. Dimberg A. Chemokines in angiogenesis[J]. Curr Top Microbiol Immunol, 2010, 341:59-80.
30. Bernardini G, Ribatti D, Spinetti G, et al. Analysis of the role of chemokines in angiogenesis[J]. J Immunol Methods, 2003, 273:83-101.
31. Murakami T, Frey T, Lin C, et al. Protein kinase Cβ phosphorylates occludin regulating tight junction trafficking in vascular endothelial growth factor-induced permeability in vivo[J]. Diabetes, 2012, 61:1573-1583.
32. Manitiu ML. The endocannabinoid system and its role in the pathogenesis and treatment of cardiovascular disturbances in cirrhosis[J]. Acta Gastroenterol Belg, 2013, 76:195-199.
33. Chiurchiù V, Lanuti M, Catanzaro G, et al. Detailed characterization of the endocannabinoid system in human macrophages and foam cells, and anti-inflammatory role of type-2 cannabinoid receptor[J]. Atherosclerosis, 2014, 233:55-63.
34. Horváth B, Mukhopadhyay P, Haskó G, et al. The endocannabinoid system and plant-derived cannabinoids in diabetes and diabetic complications[J]. Am J Pathol, 2012, 180:432-442.
35. Jenkin KA, Verty ANA, McAinch AJ, et al. Endocannabinoids and the renal proximal tubule: an emerging role in diabetic nephropathy[J]. Int J Biochem Cell Biol, 2012, 44:2028-2031.
36. Rajesh M, Bátkai S, Kechrid M, et al. Cannabinoid 1 receptor promotes cardiac dysfunction, oxidative stress, inflammation, and fibrosis in diabetic cardiomyopathy[J]. Diabetes, 2012, 61:716-727.
37. Buraczynska M, Wacinski P, Zukowski P, et al. Common polymorphism in the cannabinoid type 1 receptor gene (CNR1) is associated with microvascular complications in type 2 diabetes[J]. J Diabetes Complications, 2014, 28:35-39.
38. Lim SK, Park MJ, Lim JC, et al. Hyperglycemia induces apoptosis via CB1 activation through the decrease of FAAH 1 in retina pigment epithelial cells[J]. J Cell Physiol, 2012, 227:569-577.
39. El-Remessy AB, Rajesh M, Mukhopadhyay P, et al. Cannabinoid 1 receptor activation contributes to vascular inflammation and cell death in a mouse model of diabetic retinopathy and a human retinal cell line[J]. Diabetologia, 2011, 54:1567-1578.
40. Sapieha P, Sirinyan M, Hamel D, et al. The succinate receptor GPR91 in neurons has a major role in retinal angiogenesis[J]. Nat Med, 2008, 14:1067-1076.
41. Peti-Peterdi J. High glucose and renin release: the role of succinate and GPR91[J]. Kidney Int, 2010, 78:1214-1217.
42. Toma I, Kang JJ, Sipos A, et al. Succinate receptor GPR91 provides a direct link between high glucose levels and renin release in murine and rabbit kidney[J]. J Clin Invest, 2008, 118:2526-2534.
43. Hu JY, Wu Q, Li TT, et al. Inhibition of high glucose-induced VEGF release in retinal ganglion cells by RNA interference targeting G protein-coupled receptor 91[J]. Exp Eye Res, 2013, 109:31-39.
44. Ariza AC, Deen PM, Robben JH. The succinate receptor as a novel therapeutic target for oxidative and metabolic stress-related conditions[J/OL]. Front Endocrinol (Lausanne), 2012, 3:22[2013-10-28]. http://journal.frontiersin.org/Journal/10.3389/fendo.2012.00022/full.
45. 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, 53:2208-2217.
46. 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.
47. Digby JE, McNeill E, Dyar OJ, et al. Anti-inflammatory effects of nicotinic acid in adipocytes demonstrated by suppression of fractalkine, RANTES, and MCP-1 and upregulation of adiponectin[J]. Atherosclerosis, 2010, 209:89-95.
48. Lukasova M, Malaval C, Gille A, et al. Nicotinic acid inhibits progression of atherosclerosis in mice through its receptor GPR109A expressed by immune cells[J]. J Clin Invest, 2011, 121:1163-1173.
49. Yu XH, Tang ZB, Liu LJ, et al. Apelin and its receptor APJ in cardiovascular diseases[J]. Clin Chim Acta, 2014, 428:1-8.
50. Kang YJ, Kim JM, Anderson JP, et al. Apelin-APJ signaling is a critical regulator of endothelial MEF2 activation in cardiovascular development[J]. Circ Res, 2013, 113:22-31.
51. O'Carroll AM, Lolait SJ, Harris LE, et al. The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis[J]. J Endocrinol, 2013, 219:13-35.
52. Tao Y, Lu Q, Jiang YR, et al. Apelin in plasma and vitreous and in fibrovascular retinal membranes from patients with proliferative diabetic retinopathy[J]. Invest Ophthalmol Vis Sci, 2010, 51:4237-4242.
53. Kasai A, Ishimaru Y, Kinjo T, et al. Apelin is a crucial factor for hypoxia-induced retinal angiogenesis[J]. Arterioscler Thromb Vasc Biol, 2010, 30:2182-2187.
54. Schulte G, Bryja V. The Frizzled family of unconventional G-protein-coupled receptors[J]. Trends Pharmacol Sci, 2007, 28:518-525.
55. Sui L, Bouwens L, Mfopou JK. Signaling pathways during maintenance and definitive endoderm differentiation of embryonic stem cells[J]. Int J Dev Biol, 2013, 57:1-12.
56. Kim W, Kim M, Jho EH. Wnt/β-catenin signalling: from plasma membrane to nucleus[J]. Biochem J, 2013, 450:9-21.
57. Stewart DJ. Wnt signaling pathway in non-small cell lung cancer[J]. J Natl Cancer Inst, 2014, 106:djt356.
58. Wang YS, Rattner A, Zhou YL, et al. Norrin/Frizzled4 signaling in retinal vascular development and blood brain barrier plasticity[J]. Cell, 2012, 151:1332-1344.
59. Ye X, Wang YS, Cahill H, et al. Norrin, frizzled-4, and Lrp5 signaling in endothelial cells controls a genetic program for retinal vascularization[J]. Cell, 2009, 139:285-298.
60. Nikopoulos K, Venselaar H, Collin RWJ, et al. Overview of the mutation spectrum in familial exudative vitreoretinopathy and Norrie disease with identification of 21 novel variants in FZD4, LRP5, and NDP[J]. Hum Mutat, 2010, 31:656-666.
61. Chen Y, Hu Y, Zhou T, et al. Activation of the Wnt pathway plays a pathogenic role in diabetic retinopathy in humans and animal models[J]. Am J Pathol, 2009, 175:2676-2685.

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Chinese Journal of Ocular Fundus Diseases

视紫红质类及卷曲蛋白受体在糖尿病视网膜病变发生发展中的作用

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