Molecular and Pathophysiological Mechanisms of Diabetic Retinopathy in Relation to Adhesion Molecules

Author(s): Salini Scaria Joy , Khalid Siddiqui* .

Journal Name: Current Diabetes Reviews

Volume 15 , Issue 5 , 2019

Become EABM
Become Reviewer


Diabetic Retinopathy (DR) is considered as a most common microvascular complication of diabetes affected by one in three people who are suffered for diabetes. Several pathophysiological mechanisms and adhesion molecules may play an etiologic role in the development of diabetes and its complications. The adhesion molecules located on both leucocytes and endothelial cells and considered as important molecules which can assessed the endothelial function. The functions of adhesion molecules involved in the cellular margination, slow rolling and transmigration of leukocytes. Hyperglycemia and its immediate biochemical sequelae or the low-grade inflammation directly alter endothelial function or influence endothelial cell functioning indirectly by induce oxidative stress and activates leukocytosis and leukocyte-endothelial cell interactions by the increased expression of adhesion molecules, growth factors, inflammatory factors, chemokines etc. and results DR. This review summarized the several pathophysiological mechanisms and role of adhesion molecules in disruption of homeostasis of vasculature by leukocytes in the development of diabetic retinopathy.

Keywords: Diabetic retinopathy, endothelial dysfunction, inflammation, leucocytes, integrins, selectins, immunoglobulin superfamily, cadherins.

International Diabetes Federation. IDF Diabetes Atlas. 8th ed. Brussels, Belgium: International Diabetes Federation; 2017.
Sripriya S, Raman R, Soumittra N, et al. Current research perspectives in understanding diabetic retinopathy. Adv Vision Res 2017; pp. 259-74.
Chibber R, Ben-Mahmud BM, Chibber S, et al. Leukocytes in diabetic retinopathy. Curr Diabetes Rev 2007; 3: 3-14.
Patel N. Targeting leukostasis for the treatment of early diabetic retinopathy. Cardiovasc Hematol Disord Drug Targets 2009; 9: 222-9.
Adamis AP. Is diabetic retinopathy an inflammatory disease? Br J Ophthalmol 2002; 86: 363-5.
Rübsam A, Parikh S, Fort PE. Role of inflammation in diabetic retinopathy. Int J Mol Sci 2018; 19E942
Praidou A, Androudi S, Brazitikos P, et al. Angiogenic growth factors and their inhibitors in diabetic retinopathy. Curr Diabetes Rev 2010; 6: 304-12.
Wang W, Lo ACY. Diabetic retinopathy: Pathophysiology and treatments. Int J Mol Sci 2018; 19(6)E1816
Dagher YS, Park V, Hoehn AT, et al. Studies of rat and human retinas predict a role for the polyol pathway in human diabetic retinopathy. Diabetes 2004; 53: 2404-11.
Obrosova IG, Minchenko AG, Vasupuram R, et al. Aldose reductase inhibitor fidarestat prevents retinal oxidative stress and vascular endothelial growth factor overexpression in streptozotocin-diabetic rats. Diabetes 2003; 52: 864-71.
Lee SE, Ma W, Rattigan EM, et al. Ultrastructural features of retinal capillary basement membrane thickening in diabetic swine. Ultrastruct Pathol 2010; 34: 35-41.
Chung SSM, Chung SK. Genetic analysis of aldose reductase in diabetic complications. Curr Med Chem 2003; 10: 1375-87.
Goldin A, Beckman JA, Schmidt AM, et al. Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation 2006; 114: 597-605.
Stitt AW. Advanced glycation: an important pathological event in diabetic and age related ocular disease. Br J Ophthalmol 2001; 85: 746-53.
Stitt A, Gardiner TA, Alderson NL, et al. The AGE inhibitor pyridoxamine inhibits development of retinopathy in experimental diabetes. Diabetes 2002; 51: 2826-32.
Nakamura M, Barber AJ, Antonetti DA, et al. Excessive hexosamines block the neuroprotective effect of insulin and induce apoptosis in retinal neurons. J Biol Chem 2001; 276: 43748-55.
Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res 2010; 107: 1058-70.
Tarr JM, Kaul K, Chopra M, et al. Pathophysiology of diabetic retinopathy. ISRN Ophthalmol 2013; 2013343560
Joy SV, Scates AC, Bearelly S, et al. Ruboxistaurin, a protein kinase C β inhibitor, as an emerging treatment for diabetes microvascular complications. Ann Pharmacother 2005; 39: 1693-9.
Kowluru V, Kowluru RA. Increased oxidative stress in diabetes regulates activation of a small molecular weight G-protein, H-Ras, in the retina. Mol Vis 2007; 13: 602-10.
Behl T, Kaur I, Kotwani A. Implication of oxidative stress in progression of diabetic retinopathy. Surv Ophthalmol 2016; 61: 187-96.
Domanico D, Fragiotta S, Cutini A, et al. Circulating levels of reactive oxygen species in patients with nonproliferative diabetic retinopathy and the influence of antioxidant supplementation: 6-month follow-up. Indian J Ophthalmol 2015; 63: 9-14.
Mohammad G, Kowluru RA. Novel role of mitochondrial matrix metalloproteinase-2 in the development of diabetic retinopathy. Invest Ophthalmol Vis Sci 2011; 52: 3832-41.
van der Wijk AE, Hughes JM, Klaassen I, et al. Is leukostasis a crucial step or epiphenomenon in the pathogenesis of diabetic retinopathy? J Leukoc Biol 2017; 102: 993-1001.
Gurel Z, Sheibani N. O-Linked β-N-acetylglucosamine (O-GlcNAc) modification: A new pathway to decode pathogenesis of diabetic retinopathy. Clin Sci (Lond) 2018; 132: 185-98.
Chibber R, Ben-Mahmud BM, Coppini D, et al. Activity of the glycosylating enzyme, core 2 GlcNAc (β1,6) transferase, is higher in polymorphonuclear leukocytes from diabetic patients compared with age-matched control subjects: relevance to capillary occlusion in diabetic retinopathy. Diabetes 2000; 49: 1724-30.
Ben-Mahmud BM, Chan WH, Abdulahad RM, et al. Clinical validation of a link between TNF-alpha and the glycosylation enzyme core 2 GlcNAc-T and the relationship of this link to diabetic retinopathy. Diabetologia 2006; 49: 185-91.
Abiko T, Abiko A, Clermont AC, et al. Characterization of retinal leukostasis and hemodynamics in insulin resistance and diabetes: role of oxidants and protein kinase-C activation. Diabetes 2003; 52: 829-37.
Abcouwer SF. Angiogenic factors and cytokines in diabetic retinopathy. J Clin Cell Immunol 2013; suppl 1(11)
Barczyk M, Carracedo S, Gullberg D. Integrins. Cell Tissue Res 2010; 339: 269-80.
Santulli RJ, Kinney WA, Ghosh S, et al. Studies with an orally bioavailable alpha V integrin antagonist in animal models of ocular vasculopathy: retinal neovascularization in mice and retinal vascular permeability in diabetic rats. J Pharmacol Exp Ther 2008; 324: 894-901.
Yun JH, Park SW, Kim JH, et al. Angiopoietin 2 induces astrocyte apoptosis via αvβ5-integrin signaling in diabetic retinopathy. Cell Death Dis 2016; 18(7)e210
Ning A, Cui J, Maberley D, et al. Expression of integrins in human proliferative diabetic retinopathy membranes. Can J Ophthalmol 2008; 43: 683-8.
Song H, Wang L, Hui Y. Expression of CD18 on the neutrophils of patients with diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 2007; 245: 24-31.
Barouch FC, Miyamoto K, Allport JR, et al. Integrin mediated neutrophil adhesion and retinal leukostasis in diabetes. Invest Ophthalmol Vis Sci 2000; 41: 1153-8.
Iliaki E, Poulaki V, Mitsiades N, et al. Role of alpha 4 integrin (CD49d) in the pathogenesis of diabetic retinopathy. Invest Ophthalmol Vis Sci 2009; 50: 4898-904.
Matsubara Y, Murata M, Maruyama T, et al. Association between diabetic retinopathy and genetic variations in a2b1 integrin, a platelet receptor for collagen. Blood 2000; 95: 1560-4.
McEver RP. Selectins: initiators of leukocyte adhesion and signaling at the vascular wall. Cardiovasc Res 2015; 20: 154.
Vestweber D. How leukocytes cross the vascular endothelium. Nat Rev Immunol 2015; 15: 692-704.
Timmerman I, Daniel AE, Kroon J, et al. Leukocytes crossing the endothelium: a matter of communication. Int Rev Cell Mol Biol 2016; 322: 281-329.
MacKinnon JR, Knott RM, Forrester JV. Altered L-selectin expression in lymphocytes and increased adhesion to endothelium in patients with diabetic retinopathy. Br J Ophthalmol 2004; 88: 1137-41.
Karadayi K, Top C, Gülecek O. The relationship between soluble L-selectin and the development of diabetic retinopathy. Ocul Immunol Inflamm 2003; 11: 123-9.
Simon S, Hu Y, Vestweber D, et al. Neutrophil tethering on E-selectin activates β2 integrin binding to ICAM-1 through a mitogen-activated protein kinase signal transduction pathway. J Immunol 2000; 164: 4348-58.
Soedamah-Muthu SS, Chaturvedi N, Schalkwijk CG, et al. Soluble vascular cell adhesion molecule-1 and soluble E-selectin are associated with micro-and macrovascular complications in Type 1 diabetic patients. J Diabetes Complications 2006; 20: 188-95.
Adamiec-Mroczek J, Oficjalska-Młyńczak J, Misiuk-Hojło M. Proliferative diabetic retinopathy-The influence of diabetes control on the activation of the intraocular molecule system. Diabetes Res Clin Pract 2009; 84: 46-50.
Yun MR, Im DS, Lee JS, et al. NAD(P)H oxidase-stimulating activity of serum from type 2 diabetic patients with retinopathy mediates enhanced endothelial expression of E-selectin. Life Sci 2006; 78: 2608-14.
Kasza M, Meleg J, Vardai J, et al. Plasma E-selectin levels can play a role in the development of diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 2017; 255: 25-30.
Matsumoto K, Sera Y, Ueki Y, et al. Comparison of serum concentrations of soluble adhesion molecules in diabetic microangiopathy and macroangiopathy. Diabet Med 2002; 19: 822-6.
Blum A, Pastukh N, Socea D, et al. Levels of adhesion molecules in peripheral blood correlates with stages of diabetic retinopathy and may serve as bio markers for microvascular complications. Cytokine 2018; 106: 76-9.
Penman A, Hoadley S, Wilson JG, et al. P-selectin plasma levels and genetic variant associated with diabetic retinopathy in African Americans. Am J Ophthalmol 2015; 159: 1152-60.
Kamiuchi K, Hasegawa G, Obayashi H, et al. Intercellular adhesion molecule-1 (ICAM-1) polymorphism is associated with diabetic retinopathy in Type 2 diabetes mellitus. Diabet Med 2002; 19: 371-6.
Muller WA. Leukocyte–endothelial-cell interactions in leukocyte transmigration and the inflammatory response. Trends Immunol 2003; 24: 327-34.
Koskela UE, Kuusisto SM, Nissinen AE, et al. High vitreous concentration of IL-6 and IL-8, but not of adhesion molecules in relation to plasma concentrations in proliferative diabetic retinopathy. Ophthalmic Res 2013; 49: 108-14.
Noda K, Nakao S, Ishida S, et al. Leukocyte adhesion molecules in diabetic retinopathy. J Ophthalmol 2012; 2012: 6.
Nowak M, Wielkoszyński T, Marek B, et al. Blood serum levels of vascular cell adhesion molecule (sVCAM-1), intercellular adhesion molecule (sICAM-1) and endothelial leucocyte adhesion molecule-1 (ELAM-1) in diabetic retinopathy. Clin and Exp Med 2008; 8: 159-64.
Joussen AM, Poulald V, Qin W, et al. Retinal vascular endothelial growth factor induces intercellular adhesion molecular-1 and endothelial nitric oxide synthase expression and initiates early diabetic retinal leukocyte adhesion in vivo. Am J Pathol 2002; 160: 501-9.
Joussen AM, Poulaki V, Le ML, et al. A central role for inflammation in the pathogenesis of diabetic retinopathy. FASEB J 2004; 18: 1450-2.
Boggon TJ, Murray J, Chappuis-Flament S, et al. C-cadherin ectodomain structure and implications for cell adhesion mechanisms. Science 2002; 296: 1308-13.
Ciatto C, Bahna F, Zampieri N, et al. T-cadherin structures reveal a novel adhesive binding mechanism. Nat Struct Mol Biol 2010; 17: 339-47.
Hulpiau P, van Roy F. Molecular evolution of the cadherin superfamily. Int J Biochem Cell Biol 2009; 41: 349-69.
Navaratna D, McGuire PG, Menicucci G, et al. Proteolytic degradation of VE-cadherin alters the blood-retinal barrier in diabetes. Diabetes 2007; 56: 2380-7.
Davidson MK, Russ PK, Glick GG, et al. Reduced expression of the adherens junction protein cadherin-5 in a diabetic retina. Am J Ophthalmol 2000; 129: 267-9.
Mishra A, Newman EA. Inhibition of inducible nitric oxide synthase reverses the loss of functional hyperemia in diabetic retinopathy. Glia 2010; 58: 1996-2004.
Adamis AP, Berman AJ. Immunological mechanisms in the pathogenesis of diabetic retinopathy. Semin Immunopathol 2008; 30: 65-84.
Rangasamy S, McGuire PG, Das A. Diabetic retinopathy and inflammation: novel therapeutic targets. Middle East Afr J Ophthalmol 2012; 19: 52-9.
da Costa Martins P, García-Vallejo JJ, van Thienen JV, et al. P-Selectin glycoprotein ligand-1 is expressed on endothelial cells and mediates monocyte adhesion to activated endothelium. Arterioscler Thromb Vasc Biol 2007; 27: 1023-9.
Hidalgo A, Peired AJ, Wild M, et al. Complete identification of E-selectin ligands on neutrophils reveals distinct functions of PSGL-1, ESL-1, and CD44. Immunity 2007; 26: 477-89.
Ley K, Laudanna C, Cybulsky MI, et al. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol 2007; 7: 678-89.
Rangasamy S, McGuire PG, Nitta CF, et al. Chemokine mediated monocyte trafficking into the retina: role of inflammation in alteration of the blood-retinal barrier in diabetic retinopathy. PLoS One 2014; 9e108508
Tashimo A, Mitamura Y, Nagai S, et al. Aqueous levels of macrophage migration inhibitory factor and monocyte chemotactic protein-1 in patients with diabetic retinopathy. Diabet Med 2004; 21: 1292-7.
Katakami N, Matsuhisa M, Kaneto H, et al. Monocyte chemoattractant protein-1 (MCP1) gene polymorphism as a potential risk factor for diabetic retinopathy in Japanese patients with type 2 diabetes. Diabetes Res Clin Pract 2010; 89: e9-e12.
Vestweber D. Regulation of endothelial cell contacts during leukocyte extravasation. Curr Opin Cell Biol 2002; 14: 587-93.
Nourshargh S, Krombach F, Dejana E. The role of JAM-A and PECAM-1 in modulating leukocyte infiltration in inflamed and ischemic tissues. J Leukoc Biol 2006; 80: 714-8.
Semeraro F, Cancarini A, Rezzola S, et al. Diabetic retinopathy: vascular and inflammatory disease. J Diabetes Res 2015; 2015582060
Grant MB, Afzal A, Spoerri P, et al. The role of growth factors in the pathogenesis of diabetic retinopathy. Expert Opin Investig Drugs 2004; 13: 1275-93.
Comer GM, Ciulla TA. Pharmacotherapy for diabetic retinopathy. Curr Opin Ophthalmol 2004; 15: 508-18.
Ishida S, Usui T, Yamashiro K, et al. VEGF164 is proinflammatory in the diabetic retina. Invest Ophthalmol Vis Sci 2003; 44: 2155-62.
Zhang XL, Wen L, Chen YJ, et al. Vascular endothelial growth factor up-regulates the expression of intracellular adhesion molecule-1 in retinal endothelial cells via reactive oxygen species, but not nitric oxide. Chin Med J 2009; 122: 338-43.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [363 - 371]
Pages: 9
DOI: 10.2174/1573399814666181017103844
Price: $58

Article Metrics

PDF: 32
PRC: 1