Review Article

Possible Role of Wnt Signaling Pathway in Diabetic Retinopathy

Author(s): Sheetu Sharma, Tapan Behl*, Aayush Sehgal, Sukhbir Singh, Neelam Sharma, Saurabh Bhatia, Ahmed Al-Harassi, Simona Bungau and Ebrahim Mostafavi*

Volume 23, Issue 15, 2022

Published on: 13 September, 2022

Page: [1372 - 1380] Pages: 9

DOI: 10.2174/1389450123666220301110140

Price: $65


The core of impaired vision in working people suffering from insulin-dependent and noninsulin- dependent diabetes mellitus is diabetic retinopathy (DR). The Wnt Protein Ligands family influences various processes; this ensures the cells are able to interact and co-ordinate various mobile functions, including cell growth, division, survival, apoptosis, migration, and cell destiny. The extracellular Wnt signal activates other signals. It is seen that Wnt pathways play an important role in inflammation, oxidative stress, and angiogenesis. It has been illustrated that the canonically preserved Wnt signaling system has a vital role in the homeostasis of adulthood. Developmental disorders in each of these stages will lead to serious eye problems and eventually blindness. There is, therefore, a need to specifically organize and regulate the growth of ocular tissues. In tissue specification and polarities, axonal exhaust, and maintenance of cells, especially in the central nervous system, Wnt/frizzled pathways play an important role. Thus, Wnt route antagonists may act as have been possible therapeutic options in DR by inhibiting aberrant Wnt signals. Elaborative and continued research in this area will help in the advancement of current knowledge in the field of DR, and eventually, this can lead to the development of new therapeutic approaches.

Keywords: Diabetes mellitus, diabetic retinopathy, oxidative stress, angiogenesis, Wnt signaling pathway, canonical pathway, non-canonical pathway.

Graphical Abstract
Saeedi P, Petersohn I, Salpea P, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diab Res Clin Pract 2019; 157: 157.
Agurto C, Barriga ES, Murray V, et al. Automatic detection of diabetic retinopathy and age-related macular degeneration in digital fundus images. Invest Ophthalmol Vis Sci 2011; 52(8): 5862-71.
[] [PMID: 21666234]
Fong DS, Aiello L, Gardner TW, et al. Retinopathy in diabetes. Diabetes Care 2004; 27 (Suppl. 1): s84-7.
[] [PMID: 14693935]
Gupta A, Shah K, Oza MJ, Behl T. Reactivation of p53 gene by MDM2 inhibitors: A novel therapy for cancer treatment. Biomed Pharmacother 2019; 109: 484-92.
[] [PMID: 30551517]
Malekar P, Hagenmueller M, Anyanwu A, et al. WNT signalling is critical for maladaptive cardiac hypertrophy and accelerates myocardial remodeling. Hypertension 2010; 55(4): 939-45.
Behl T, Kotwani A. Possible role of endostatin in the antiangiogenic therapy of diabetic retinopathy. Life Sci 2015; 135: 131-7.
[] [PMID: 26141993]
Clevers H, Nusse R. Wnt/β-catenin signaling and disease. Cell 2012; 149(6): 1192-205.
[] [PMID: 22682243]
Oliva CA, Montecinos-Oliva C, Inestrosa NC. WNT signalling in the central nervous system: New insights in health and disease.Progress in Molecular Biology and Translational Science. Elsevier 2018; pp. 81-130.
Nusse R. Wnt signaling in disease and in development. Cell Res 2005; 15(1): 28-32.
[] [PMID: 15686623]
Hosseini V, Dani C, Geranmayeh MH, Mohammadzadeh F, Nazari SAS, Darabi M. Wnt lipidation: Roles in trafficking, modulation, and function. J Cell Physiol 2019; 234(6): 8040-54.
[] [PMID: 30341908]
Habas R, Dawid IB. Dishevelled and Wnt signaling: Is the nucleus the final frontier? J Biol 2005; 4(1): 2.
[] [PMID: 15720723]
Komiya Y, Habas R. Wnt signal transduction pathways. Organogenesis 2008; 4(2): 68-75.
[] [PMID: 19279717]
Minde DP, Radli M, Forneris F, et al. Large extent of disorder in adenomatous polyposis coli offers a strategy to guard Wnt signalling against point mutations. PLoS ONE 2013; 8(10): e77257.
MacDonald BT, Tamai K, He X. Wnt/β-catenin signaling: Components, mechanisms, and diseases. Dev Cell 2009; 17(1): 9-26.
[] [PMID: 19619488]
Rao TP, Kühl M. An updated overview on Wnt signaling pathways: A prelude for more. Circ Res 2010; 106(12): 1798-806.
[] [PMID: 20576942]
Bilić J, Huang YL, Davidson G, et al. Wnt induces LRP6 signalosomes and promotes dishevelled-dependent LRP6 phosphorylation. Science 2007; 316(5831): 1619-22.
[] [PMID: 17569865]
Näthke I. APC at a glance. J Cell Sci 2004; 117(21): 4873-5.
[] [PMID: 15456841]
Chen Q, Ma J. Canonical Wnt signaling in diabetic retinopathy. Vision Res 2017; 139: 47-58.
[] [PMID: 28545982]
Nakamura REI, Hunter DD, Yi H, Brunken WJ, Hackam AS. Identification of two novel activities of the Wnt signaling regulator Dickkopf 3 and characterization of its expression in the mouse retina. BMC Cell Biol 2007; 8(1): 52.
[] [PMID: 18093317]
Corda G, Sala A. Non-canonical WNT/PCP signalling in cancer: Fzd6 takes centre stage. Oncogenesis 2017; 6(7): e364.
[] [PMID: 28737757]
De Calisto J, Araya C, Marchant L, Riaz CF, Mayor R. Essential role of non-canonical Wnt signalling in neural crest migration. Development 2005; 132(11): 2587-97.
[] [PMID: 15857909]
Veeman MT, Axelrod JD, Moon RT. A second canon. Functions and mechanisms of beta-catenin-independent Wnt signaling. Dev Cell 2003; 5(3): 367-77.
[] [PMID: 12967557]
Colosimo PF, Liu X, Kaplan NA, Tolwinski NS. GSK3β affects apical-basal polarity and cell-cell adhesion by regulating aPKC levels. Dev Dyn 2009; 21963.
[] [PMID: 19422025]
Slusarski DC, Pelegri F. Calcium signaling in vertebrate embryonic patterning and morphogenesis. Dev Biol 2007; 307(1): 1-13.
[] [PMID: 17531967]
Pataki CA, Couchman JR, Brábek J. Wnt signaling cascades and the roles of syndecan proteoglycans. J Histochem Cytochem 2015; 63(7): 465-80.
[] [PMID: 25910817]
Kohn AD, Moon RT. Wnt and calcium signaling: β-Catenin-independent pathways. Cell Calcium 2005; 38(3-4): 439-46.
[] [PMID: 16099039]
Ng L, Kaur P, Bunnag N, et al. WNT signaling in disease. Cells 2019; 8(8): 826.
[] [PMID: 31382613]
Durham JT, Herman IM. Microvascular modifications in diabetic retinopathy. Curr Diab Rep 2011; 11(4): 253-64.
[] [PMID: 21611764]
Antonetti DA, Klein R, Gardner TW. Diabetic retinopathy. N Engl J Med 2012; 366(13): 1227-39.
[] [PMID: 22455417]
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. Am J Pathol 2009; 175(6): 2676-85.
Barber AJ, Antonetti DA, Kern TS, et al. The Ins2Akita mouse as a model of early retinal complications in diabetes. Invest Ophthalmol Vis Sci 2005; 46(6): 2210-8.
[] [PMID: 15914643]
Isoda T, Nakatsu Y, Yamauchi K, et al. Abnormality in Wnt signaling is causatively associated with oxidative stress-induced intestinal tumorigenesis in MUTYH-null mice. Int J Biol Sci 2014; 10(8): 940-7.
[] [PMID: 25170306]
Pacher P, Obrosova I, Mabley J, Szabó C. Role of nitrosative stress and peroxynitrite in the pathogenesis of diabetic complications. Emerging new therapeutical strategies. Curr Med Chem 2005; 12(3): 267-75.
[] [PMID: 15723618]
Kiss L, Szabó C. The pathogenesis of diabetic complications: The role of DNA injury and poly(ADP-ribose) polymerase activation in peroxynitrite-mediated cytotoxicity. Mem Inst Oswaldo Cruz 2005; 100 (Suppl. 1): 29-37.
[] [PMID: 15962096]
Adamis AP, Berman AJ. Immunological mechanisms in the pathogenesis of diabetic retinopathy. Semin Immunopathol 2008; 30(2): 65-84.
[] [PMID: 18340447]
Zhang B, Abreu JG, Zhou K, et al. Blocking the Wnt pathway, a unifying mechanism for an angiogenic inhibitor in the serine proteinase inhibitor family. Proc Natl Acad Sci USA 2010; 107(15): 6900-5.
[] [PMID: 20351274]
Chibber R, Ben-Mahmud B, Chibber S, Kohner E. Leukocytes in diabetic retinopathy. Curr Diabetes Rev 2007; 3(1): 3-14.
[] [PMID: 18220651]
Gustafson B, Smith U. Cytokines promote Wnt signaling and inflammation and impair the normal differentiation and lipid accumulation in 3T3-L1 preadipocytes. J Biol Chem 2006; 281(14): 9507-16.
[] [PMID: 16464856]
Zhang SX, Wang JJ, Gao G, Shao C, Mott R, Ma J. Pigment epithelium‐derived factor (PEDF) is an endogenous antiinflammatory factor. FASEB J 2006; 20(2): 323-5.
[] [PMID: 16368716]
Ferrara N. Vascular endothelial growth factor: Basic science and clinical progress. Endocr Rev 2004; 25(4): 581-611.
[] [PMID: 15294883]
Liu Z, Habener JF. Glucagon-like peptide-1 activation of TCF7L2-dependent Wnt signaling enhances pancreatic beta cell proliferation. J Biol Chem 2008; 283(13): 8723-35.
[] [PMID: 18216022]
Hino S, Tanji C, Nakayama KI, Kikuchi A. Phosphorylation of β-catenin by cyclic AMP-dependent protein kinase stabilizes β-catenin through inhibition of its ubiquitination. Mol Cell Biol 2005; 25(20): 9063-72.
[] [PMID: 16199882]
Yi F, Sun J, Lim GE, Fantus IG, Brubaker PL, Jin T. Cross talk between the insulin and Wnt signaling pathways: Evidence from intestinal endocrine L cells. Endocrinology 2008; 149(5): 2341-51.
[] [PMID: 18258680]
Patel S, Doble B, Woodgett JR. Glycogen synthase kinase-3 in insulin and Wnt signalling: A double-edged sword? Biochem Soc Trans 2004; 32(5): 803-8.
[] [PMID: 15494020]
Okada T, Liew CW, Hu J, et al. Insulin receptors in β-cells are critical for islet compensatory growth response to insulin resistance. Proc Natl Acad Sci USA 2007; 104(21): 8977-82.
[] [PMID: 17416680]
Desbois-Mouthon C, Cadoret A, Blivet-Van MJ, et al. Insulin and IGF-1 stimulate the β-catenin pathway through two signalling cascades involving GSK-3β inhibition and Ras activation. Oncogene 2001; 20(2): 252-9.
[] [PMID: 11313952]
Carvell M, Marsh P, Persaud S, Jones P. E-cadherin interactions regulate β-cell proliferation in islet-like structures. Cell Physiol Biochem 2007; 20(5): 617-26.
[] [PMID: 17762188]
Dai C, Huh CG, Thorgeirsson SS, Liu Y. β-cell-specific ablation of the hepatocyte growth factor receptor results in reduced islet size, impaired insulin secretion, and glucose intolerance Am J Pathol 2005; 167(2): 429-36.
[] [PMID: 16049329]
Apte U, Zeng G, Muller P, et al. Activation of Wnt/β-catenin pathway during hepatocyte growth factor-induced hepatomegaly in mice. Hepatology 2006; 44(4): 992-1002.
[] [PMID: 17006939]
Buteau J, Accili D. Regulation of pancreatic? cell function by the forkhead protein FoxO1. Diabetes Obes Metab 2007; 9(s2) (Suppl. 2): 140-6.
[] [PMID: 17919188]
Zhang B, Hu Y, Ma J. Anti-inflammatory and antioxidant effects of SERPINA3K in the retina. Invest Ophthalmol Vis Sci 2009; 50(8): 3943-52.
[] [PMID: 19324842]
Liu Q, Li J, Cheng R, et al. Nitrosative stress plays an important role in Wnt pathway activation in diabetic retinopathy. Antioxid Redox Signal 2013; 18(10): 1141-53.
[] [PMID: 23066786]
Jenkins AJ, McBride JD, Januszewski AS, et al. Increased serum kallistatin levels in type 1 diabetes patients with vascular complications. J Angiogenes Res 2010; 2(1): 19.
[] [PMID: 20860825]
Matsuoka M, Ogata N, Minamino K, Matsumura M. Expression of pigment epithelium-derived factor and vascular endothelial growth factor in fibrovascular membranes from patients with proliferative diabetic retinopathy. Jpn J Ophthalmol 2006; 50(2): 116-20.
[] [PMID: 16604386]
Park K, Jin J, Hu Y, Zhou K, Ma J. Overexpression of pigment epithelium-derived factor inhibits retinal inflammation and neovascularization. Am J Pathol 2011; 178(2): 688-98.
[] [PMID: 21281801]
Huang KM, Dentchev T, Stambolian D. MiRNA expression in the eye. Mamm Genome 2008; 19(7-8): 510-6.
[] [PMID: 18648874]
Jiang A, Hu W, Meng H, Gao H, Qiao X. Loss of VLDL receptor activates retinal vascular endothelial cells and promotes angiogenesis. Invest Ophthalmol Vis Sci 2009; 50(2): 844-50.
[] [PMID: 18936153]
Lee K, Hu Y, Ding L, et al. Therapeutic potential of a monoclonal antibody blocking the Wnt pathway in diabetic retinopathy. Diabetes 2012; 61(11): 2948-57.
[] [PMID: 22891217]
Hu W, Jiang A, Liang J, et al. Expression of VLDLR in the retina and evolution of subretinal neovascularization in the knockout mouse model’s retinal angiomatous proliferation. Invest Ophthalmol Vis Sci 2008; 49(1): 407-15.
[] [PMID: 18172119]
Huang Q, Wang S, Sorenson CM, Sheibani N. PEDF-deficient mice exhibit an enhanced rate of retinal vascular expansion and are more sensitive to hyperoxia-mediated vessel obliteration. Exp Eye Res 2008; 87(3): 226-41.
[] [PMID: 18602915]
Takahashi Y, Chen Q, Rajala RVS, Ma J. MicroRNA-184 modulates canonical Wnt signaling through the regulation of frizzled-7 expression in the retina with ischemia-induced neovascularization. FEBS Lett 2015; 589(10): 1143-9.
[] [PMID: 25796186]
Hashimi ST, Fulcher JA, Chang MH, Gov L, Wang S, Lee B. MicroRNA profiling identifies miR-34a and miR-21 and their target genes JAG1 and WNT1 in the coordinate regulation of dendritic cell differentiation. Blood 2009; 114(2): 404-14.
[] [PMID: 19398721]
Bufe A, del Arco AG, Hennecke M-I, et al. Wnt signaling recruits KIF2A to the spindle to ensure chromosome congression and alignment during mitosis. Cold Spring Harbor Laboratory 2020.
MacDonald BT, Yokota C, Tamai K, Zeng X, He X. Wnt signal amplification via activity, cooperativity, and regulation of multiple intracellular PPPSP motifs in the Wnt co-receptor LRP6. J Biol Chem 2008; 283(23): 16115-23.
[] [PMID: 18362152]
Noma H, Funatsu H, Yamashita H, Kitano S, Mishima HK, Hori S. Regulation of angiogenesis in diabetic retinopathy: Possible balance between vascular endothelial growth factor and endostatin. Arch Ophthalmol 2002; 120(8): 1075-80.
[] [PMID: 12149062]
Endo M, Yanagisawa K, Tsuchida K, et al. Increased levels of vascular endothelial growth factor and advanced glycation end products in aqueous humor of patients with diabetic retinopathy. Horm Metab Res 2001; 33(5): 317-22.
[] [PMID: 11440280]
Yiu WH, Li Y, Lok SWY, et al. Protective role of kallistatin in renal fibrosis via modulation of Wnt/β-catenin signaling. Clin Sci (Lond) 2021; 135(3): 429-46.
[] [PMID: 33458750]
Rechtman E, Harris A, Garzozi HJ, Ciulla TA. Pharmacologic therapies for diabetic retinopathy and diabetic macular edema. Clin Ophthalmol 2007; 1(4): 383-91.
[PMID: 19668515]
Titchenell PM, Antonetti DA. Using the past to inform the future: Anti-VEGF therapy as a road map to develop novel therapies for diabetic retinopathy. Diabetes 2013; 62(6): 1808-15.
[] [PMID: 23704522]
Dejana E. The role of WNT signalling in physiological and pathological angiogenesis.Circ Res. 2010; 107: pp. (8)943-52.
Toomes C, Bottomley HM, Jackson RM, et al. Mutations in LRP5 or FZD4 underlie the common familial exudative vitreoretinopathy locus on chromosome 11q. Am J Hum Genet 2004; 74(4): 721-30.
[] [PMID: 15024691]
Choi HJ, Park H, Lee HW, Kwon YG. The Wnt pathway and the roles for its antagonists, DKKS, in angiogenesis. IUBMB Life 2012; 64(9): 724-31.
[] [PMID: 22807036]
Park K, Lee K, Zhang B, et al. Identification of a novel inhibitor of the canonical Wnt pathway. Mol Cell Biol 2011; 31(14): 3038-51.
[] [PMID: 21576363]
Bats ML, Bougaran P, Peghaire C, et al. Therapies targeting Frizzled‐7/β‐catenin pathway prevent the development of pathological angiogenesis in an ischemic retinopathy model. FASEB J 2020; 34(1): 1288-303.
[] [PMID: 31914666]
Pinna A, Emanueli C, Dore S, Salvo M, Madeddu P, Carta F. Levels of human tissue kallikrein in the vitreous fluid of patients with severe proliferative diabetic retinopathy. Ophthalmologica 2004; 218(4): 260-3.
[] [PMID: 15258415]
Chao J, Li P, Chao L. Kallistatin: Double-edged role in angiogenesis, apoptosis and oxidative stress. Biol Chem 2017; 398(12): 1309-17.
[] [PMID: 28742513]
Tang L, Zhang C, Yang Q, et al. Melatonin maintains inner blood‐retinal barrier via inhibition of p38/TXNIP/NF‐κB pathway in diabetic retinopathy. J Cell Physiol 2021; 236(8): 5848-64.
[] [PMID: 33432588]

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