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Cardiovascular Diabetology
Published in: Cardiovascular Diabetology 1/2024

Open Access 01-12-2024 | Diabetic Retinopathy | Research

Heparanase inhibition as a systemic approach to protect the endothelial glycocalyx and prevent microvascular complications in diabetes

Authors: Monica Gamez, Hesham E. Elhegni, Sarah Fawaz, Kwan Ho Ho, Neill W. Campbell, David A. Copland, Karen L. Onions, Matthew J. Butler, Elizabeth J. Wasson, Michael Crompton, Raina D. Ramnath, Yan Qiu, Yu Yamaguchi, Kenton P. Arkill, David O. Bates, Jeremy E. Turnbull, Olga V. Zubkova, Gavin I. Welsh, Denize Atan, Simon C. Satchell, Rebecca R. Foster

Published in: Cardiovascular Diabetology | Issue 1/2024

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Abstract

Background

Diabetes mellitus is a chronic disease which is detrimental to cardiovascular health, often leading to secondary microvascular complications, with huge global health implications. Therapeutic interventions that can be applied to multiple vascular beds are urgently needed. Diabetic retinopathy (DR) and diabetic kidney disease (DKD) are characterised by early microvascular permeability changes which, if left untreated, lead to visual impairment and renal failure, respectively. The heparan sulphate cleaving enzyme, heparanase, has previously been shown to contribute to diabetic microvascular complications, but the common underlying mechanism which results in microvascular dysfunction in conditions such as DR and DKD has not been determined.

Methods

In this study, two mouse models of heparan sulphate depletion (enzymatic removal and genetic ablation by endothelial specific Exotosin-1 knock down) were utilized to investigate the impact of endothelial cell surface (i.e., endothelial glycocalyx) heparan sulphate loss on microvascular barrier function. Endothelial glycocalyx changes were measured using fluorescence microscopy or transmission electron microscopy. To measure the impact on barrier function, we used sodium fluorescein angiography in the eye and a glomerular albumin permeability assay in the kidney. A type 2 diabetic (T2D, db/db) mouse model was used to determine the therapeutic potential of preventing heparan sulphate damage using treatment with a novel heparanase inhibitor, OVZ/HS-1638. Endothelial glycocalyx changes were measured as above, and microvascular barrier function assessed by albumin extravasation in the eye and a glomerular permeability assay in the kidney.

Results

In both models of heparan sulphate depletion, endothelial glycocalyx depth was reduced and retinal solute flux and glomerular albumin permeability was increased. T2D mice treated with OVZ/HS-1638 had improved endothelial glycocalyx measurements compared to vehicle treated T2D mice and were simultaneously protected from microvascular permeability changes associated with DR and DKD.

Conclusion

We demonstrate that endothelial glycocalyx heparan sulphate plays a common mechanistic role in microvascular barrier function in the eye and kidney. Protecting the endothelial glycocalyx damage in diabetes, using the novel heparanase inhibitor OVZ/HS-1638, effectively prevents microvascular permeability changes associated with DR and DKD, demonstrating a novel systemic approach to address diabetic microvascular complications.
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Literature
1.
Gheith O, Farouk N, Nampoory N, Halim MA, Al-Otaibi T. Diabetic kidney disease: world wide difference of prevalence and risk factors. J Nephropharmacol. 2015;5(1):49–56.PubMedPubMedCentral
2.
Teo ZL, Tham YC, Yu M, Chee ML, Rim TH, Cheung N, et al. Global prevalence of diabetic retinopathy and projection of burden through 2045: systematic review and meta-analysis. Ophthalmology. 2021 Nov;128(11):1580-1591. doi: 10.1016/j.ophtha.2021.04.027CrossRefPubMed
3.
4.
5.
Xue R, Gui D, Zheng L, Zhai R, Wang F, Wang N. Mechanistic insight and management of diabetic nephropathy: recent progress and future perspective. J Diabetes Res. 2017;2017:1839809.PubMedPubMedCentralCrossRef
6.
Dinneen SF, Gerstein HC. The association of microalbuminuria and mortality in non-insulin-dependent diabetes mellitus. A systematic overview of the literature. Arch Intern Med. 1997;157(13):1413–8.PubMedCrossRef
7.
Allen KV, Walker JD. Microalbuminuria and mortality in long-duration type 1 diabetes. Diabetes Care. 2003;26(8):2389–91.PubMedCrossRef
8.
Klein R, Zinman B, Gardiner R, Suissa S, Donnelly SM, Sinaiko AR, et al. The relationship of diabetic retinopathy to preclinical diabetic glomerulopathy lesions in type 1 diabetic patients: the renin-angiotensin system study. Diabetes. 2005;54(2):527–33.PubMedCrossRef
9.
Kotlarsky P, Bolotin A, Dorfman K, Knyazer B, Lifshitz T, Levy J. Link between retinopathy and nephropathy caused by complications of diabetes mellitus type 2. Int Ophthalmol. 2015;35(1):59–66.PubMedCrossRef
10.
Lee WJ, Sobrin L, Lee MJ, Kang MH, Seong M, Cho H. The relationship between diabetic retinopathy and diabetic nephropathy in a population-based study in Korea (KNHANES V-2, 3). Invest Ophthalmol Vis Sci. 2014;55(10):6547–53.PubMedCrossRef
11.
Yamanouchi M, Mori M, Hoshino J, Kinowaki K, Fujii T, Ohashi K, et al. Retinopathy progression and the risk of end-stage kidney disease: results from a longitudinal Japanese cohort of 232 patients with type 2 diabetes and biopsy-proven diabetic kidney disease. BMJ Open Diabetes Res Care. 2019;7(1): e000726.PubMedPubMedCentralCrossRef
12.
Group UPDS (UKPDS). Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352(9131):837–53.CrossRef
13.
Stitt AW, Curtis TM, Chen M, Medina RJ, McKay GJ, Jenkins A, et al. The progress in understanding and treatment of diabetic retinopathy. Prog Retin Eye Res. 2016;51:156–86.PubMedCrossRef
14.
15.
Fong DS, Aiello L, Gardner TW, King GL, Blankenship G, Cavallerano JD, et al. Retinopathy in diabetes. Diabetes Care. 2004;27(suppl_1):s84–7.PubMedCrossRef
16.
Selby NM, Taal MW. An updated overview of diabetic nephropathy: diagnosis, prognosis, treatment goals and latest guidelines. Diabetes Obes Metab. 2020;22(S1):3–15.PubMedCrossRef
17.
Salmon AH, Satchell SC. Endothelial glycocalyx dysfunction in disease: albuminuria and increased microvascular permeability. J Pathol. 2012;226(4):562–74.PubMedCrossRef
18.
Reitsma S, Slaaf DW, Vink H, Van Zandvoort MA, oude Egbrink MG. The endothelial glycocalyx: composition, functions, and visualization. Pflugers Arch. 2007;454(3):345–59.PubMedPubMedCentralCrossRef
19.
Zeng Y, Waters M, Andrews A, Honarmandi P, Ebong EE, Rizzo V, et al. Fluid shear stress induces the clustering of heparan sulfate via mobility of glypican-1 in lipid rafts. Am J Physiol Heart Circ Physiol. 2013;305(6):H811–20.PubMedPubMedCentralCrossRef
20.
Constantinescu AA, Vink H, Spaan JAE. Endothelial cell glycocalyx modulates immobilization of leukocytes at the endothelial surface. Arterioscler Thromb Vasc Biol. 2003;23(9):1541–7.PubMedCrossRef
21.
Nieuwdorp M, van Haeften TW, Gouverneur MCLG, Mooij HL, van Lieshout MHP, Levi M, et al. Loss of endothelial glycocalyx during acute hyperglycemia coincides with endothelial dysfunction and coagulation activation in vivo. Diabetes. 2006;55(2):480–6.PubMedCrossRef
22.
23.
Duncan G, McCormick C, Tufaro F. The link between heparan sulfate and hereditary bone disease: finding a function for the EXT family of putative tumor suppressor proteins. J Clin Invest. 2001;108(4):511–6.PubMedPubMedCentralCrossRef
24.
Manon-Jensen T, Itoh Y, Couchman JR. Proteoglycans in health and disease: the multiple roles of syndecan shedding. FEBS J. 2010;277(19):3876–89.PubMedCrossRef
25.
Ramnath RD, Butler MJ, Newman G, Desideri S, Russell A, Lay AC, et al. Blocking matrix metalloproteinase-mediated syndecan-4 shedding restores the endothelial glycocalyx and glomerular filtration barrier function in early diabetic kidney disease. Kidney Int. 2020;97(5):951–65.PubMedPubMedCentralCrossRef
26.
van den Hoven MJ, Rops AL, Bakker MA, Aten J, Rutjes N, Roestenberg P, et al. Increased expression of heparanase in overt diabetic nephropathy. Kidney Int. 2006;70(12):2100–8.PubMedCrossRef
27.
Zhao Y, Liu J, Ten S, Zhang J, Yuan Y, Yu J, et al. Plasma heparanase is associated with blood glucose levels but not urinary microalbumin excretion in type 2 diabetic nephropathy at the early stage. Ren Fail. 2017;39(1):698–701.PubMedPubMedCentralCrossRef
28.
El-Asrar AMA, Alam K, Nawaz MI, Mohammad G, den Eynde KV, Siddiquei MM, et al. Upregulated expression of heparanase in the vitreous of patients with proliferative diabetic retinopathy originates from activated endothelial cells and leukocytes. Invest Ophthalmol Vis Sci. 2015;56(13):8239–47.PubMedCrossRef
29.
Zubkova OV, Ahmed YA, Guimond SE, Noble SL, Miller JH, Alfred Smith RA, et al. Dendrimer heparan sulfate glycomimetics: potent heparanase inhibitors for anticancer therapy. ACS Chem Biol. 2018;13(12):3236–42.PubMedCrossRef
30.
Inatani M, Irie F, Plump AS, Tessier-Lavigne M, Yamaguchi Y. Mammalian brain morphogenesis and midline axon guidance require heparan sulfate. Science. 2003;302(5647):1044–6.ADSPubMedCrossRef
31.
Oltean S, Qiu Y, Ferguson JK, Stevens M, Neal C, Russell A, et al. Vascular endothelial growth factor-A165b is protective and restores endothelial glycocalyx in diabetic nephropathy. J Am Soc Nephrol. 2015;26(8):1889–904.PubMedCrossRef
32.
Kobayashi H, Yoo TM, Kim IS, Kim MK, Le N, Webber KO, et al. L-lysine effectively blocks renal uptake of 125I- or 99mTc-labeled anti-Tac disulfide-stabilized Fv fragment. Cancer Res. 1996;56(16):3788–95.PubMed
33.
Jenniskens GJ, Oosterhof A, Brandwijk R, Veerkamp JH, van Kuppevelt TH. Heparan sulfate heterogeneity in skeletal muscle basal lamina: demonstration by phage display-derived antibodies. J Neurosci. 2000;20(11):4099–111.PubMedPubMedCentralCrossRef
34.
Dennissen MABA, Jenniskens GJ, Pieffers M, Versteeg EMM, Petitou M, Veerkamp JH, et al. Large, tissue-regulated domain diversity of heparan sulfates demonstrated by phage display antibodies*. J Biol Chem. 2002;277(13):10982–6.PubMedCrossRef
35.
Thompson SM, Fernig DG, Jesudason EC, Losty PD, van de Westerlo EMA, van Kuppevelt TH, et al. Heparan sulfate phage display antibodies identify distinct epitopes with complex binding characteristics. J Biol Chem. 2009;284(51):35621–31.PubMedPubMedCentralCrossRef
36.
Crompton M, Ferguson JK, Ramnath RD, Onions KL, Ogier AS, Gamez M, et al. Mineralocorticoid receptor antagonism in diabetes reduces albuminuria by preserving the glomerular endothelial glycocalyx. JCI Insight. 2023;8(5): e154164.PubMedPubMedCentralCrossRef
37.
Butler MJ, Ramnath R, Kadoya H, Desposito D, Riquier-Brison A, Ferguson JK, et al. Aldosterone induces albuminuria via matrix metalloproteinase–dependent damage of the endothelial glycocalyx. Kidney Int. 2019;95(1):94–107.PubMedCrossRef
38.
Allen CL, Malhi NK, Whatmore JL, Bates DO, Arkill KP. Non-invasive measurement of retinal permeability in a diabetic rat model. Microcirculation. 2020;27(6): e12623.PubMedCrossRef
39.
Desideri S, Onions KL, Qiu Y, Ramnath RD, Butler MJ, Neal CR, et al. A novel assay provides sensitive measurement of physiologically relevant changes in albumin permeability in isolated human and rodent glomeruli. Kidney Int. 2018;93(5):1086–97.PubMedPubMedCentralCrossRef
40.
Ebong EE, Macaluso FP, Spray DC, Tarbell JM. Imaging the endothelial glycocalyx in vitro by rapid freezing/freeze substitution transmission electron microscopy. Arterioscler Thromb Vasc Biol. 2011;31(8):1908–15.PubMedPubMedCentralCrossRef
41.
van den Hoven MJ, Wijnhoven TJ, Li JP, Zcharia E, Dijkman HB, Wismans RG, et al. Reduction of anionic sites in the glomerular basement membrane by heparanase does not lead to proteinuria. Kidney Int. 2008;73(3):278–87.PubMedCrossRef
42.
Lazzara MJ, Deen WM. Model of albumin reabsorption in the proximal tubule. Am J Physiol Ren Physiol. 2007;292(1):F430–9.CrossRef
43.
Khalil R, Boels MGS, Bezuijen A, Boers JE, de Bruin PC, van Dijk MAAM, et al. Mutations in the heparan sulfate backbone elongating enzymes EXT1 and EXT2 have no major effect on endothelial glycocalyx and the glomerular filtration barrier. Mol Genet Genomics. 2022;297(2):397–405.PubMedPubMedCentralCrossRef
44.
45.
Mogensen CE, Vittinghus E, Sølling K. Abnormal albumin excretion after two provocative renal tests in diabetes: physical exercise and lysine injection. Kidney Int. 1979;16(3):385–93.PubMedCrossRef
46.
Goldberg R, Rubinstein AM, Gil N, Hermano E, Li JP, van der Vlag J, et al. Role of heparanase-driven inflammatory cascade in pathogenesis of diabetic nephropathy. Diabetes. 2014;63(12):4302–13.PubMedCrossRef
47.
Vinores SA, Gadegbeku C, Campochiaro PA, Green WR. Immunohistochemical localization of blood-retinal barrier breakdown in human diabetics. Am J Pathol. 1989;134(2):231–5.PubMedPubMedCentral
48.
Vinores SA, Campochiaro PA, Lee A, McGehee R, Gadegbeku C, Green WR. Localization of blood-retinal barrier breakdown in human pathologic specimens by immunohistochemical staining for albumin. Lab Invest. 1990;62(6):742–50.PubMed
49.
Murata T, Ishibashi T, Inomata H. Immunohistochemical detection of extravasated fibrinogen (fibrin) in human diabetic retina. Graefes Arch Clin Exp Ophthalmol. 1992;230(5):428–31.PubMedCrossRef
50.
51.
Bruno G, Merletti F, Biggeri A, Bargero G, Ferrero S, Pagano G, et al. Progression to overt nephropathy in type 2 diabetes: the Casale Monferrato Study. Diabetes Care. 2003;26(7):2150–5.PubMedCrossRef
52.
Clark SJ, Keenan TDL, Fielder HL, Collinson LJ, Holley RJ, Merry CLR, et al. Mapping the differential distribution of glycosaminoglycans in the adult human retina, choroid, and sclera. Invest Ophthalmol Vis Sci. 2011;52(9):6511–21.PubMedPubMedCentralCrossRef
53.
Niemelä H, Elima K, Henttinen T, Irjala H, Salmi M, Jalkanen S. Molecular identification of PAL-E, a widely used endothelial-cell marker. Blood. 2005;106(10):3405–9.PubMedCrossRef
54.
Witmer AN, van den Born J, Vrensen GFJM, Schlingemann RO. Vascular localization of heparan sulfate proteoglycans in retinas of patients with diabetes mellitus and in VEGF-induced retinopathy using domain-specific antibodies. Curr Eye Res. 2001;22(3):190–7.PubMedCrossRef
55.
Goldberg S, Harvey SJ, Cunningham J, Tryggvason K, Miner JH. Glomerular filtration is normal in the absence of both agrin and perlecan–heparan sulfate from the glomerular basement membrane. Nephrol Dial Transplant. 2009;24(7):2044–51.PubMedPubMedCentralCrossRef
56.
57.
Roscioni SS, Heerspink HJL, de Zeeuw D. Microalbuminuria: target for renoprotective therapy PRO. Kidney Int. 2014;86(1):40–9.PubMedCrossRef
58.
Touzani F, Geers C, Pozdzik A. Intravitreal injection of Anti-VEGF antibody induces glomerular endothelial cells injury. Case Rep Nephrol. 2019;21(2019):2919080.
59.
Hanna RM, Lopez EA, Hasnain H, Selamet U, Wilson J, Youssef PN, et al. Three patients with injection of intravitreal vascular endothelial growth factor inhibitors and subsequent exacerbation of chronic proteinuria and hypertension. Clin Kidney J. 2018;12(1):92–100.PubMedPubMedCentralCrossRef
60.
Gil N, Goldberg R, Neuman T, Garsen M, Zcharia E, Rubinstein AM, et al. Heparanase is essential for the development of diabetic nephropathy in mice. Diabetes. 2012;61(1):208–16.PubMedCrossRef
61.
Bernard D, Méhul B, Delattre C, Simonetti L, Thomas-Collignon A, Schmidt R. Purification and characterization of the endoglycosidase heparanase 1 from human plantar stratum corneum: a key enzyme in epidermal physiology? J Invest Dermatol. 2001;117(5):1266–73.PubMedCrossRef
62.
D’Souza SS, Daikoku T, Farach-Carson MC, Carson DD. Heparanase expression and function during early pregnancy in mice. Biol Reprod. 2007;77(3):433–41.PubMedCrossRef
63.
64.
Rivara S, Milazzo FM, Giannini G. Heparanase: a rainbow pharmacological target associated to multiple pathologies including rare diseases. Future Med Chem. 2016;8(6):647–80.PubMedCrossRef
65.
Hammond E, Haynes NM, Cullinane C, Brennan TV, Bampton D, Handley P, et al. Immunomodulatory activities of pixatimod: emerging nonclinical and clinical data, and its potential utility in combination with PD-1 inhibitors. J Immunother Cancer. 2018;6(1):54.PubMedPubMedCentralCrossRef
66.
Tyler PC, Guimond SE, Turnbull JE, Zubkova OV. Single-entity heparan sulfate glycomimetic clusters for therapeutic applications. Angew Chem Int Ed. 2015;54(9):2718–23.CrossRef
67.
Ferro V, Liu L, Johnstone KD, Wimmer N, Karoli T, Handley P, et al. Discovery of PG545: a highly potent and simultaneous inhibitor of angiogenesis, tumor growth, and metastasis. J Med Chem. 2012;55(8):3804–13.PubMedCrossRef
68.
Spijkers-Shaw S, Campbell K, Shields NJ, Miller JH, Rendle PM, Jiao W, et al. Synthesis of novel glycolipid mimetics of heparan sulfate and their application in colorectal cancer treatment in a mouse model. Chem Asian J. 2022;17(12): e202200228.PubMedPubMedCentralCrossRef
69.
Peck T, Davis C, Lenihan-Geels G, Griffiths M, Spijkers-Shaw S, Zubkova OV, et al. The novel HS-mimetic, Tet-29, regulates immune cell trafficking across barriers of the CNS during inflammation. J Neuroinflammation. 2023;20(1):251.PubMedPubMedCentralCrossRef
70.
Smith RAA, Luo X, Lu X, Tan TC, Le BQ, Zubkova OV, et al. Enhancing BMP-2-mediated osteogenesis with a synthetic heparan sulfate mimetic. Biomater Adv. 2023;1(155): 213671.CrossRef
Metadata
Title
Heparanase inhibition as a systemic approach to protect the endothelial glycocalyx and prevent microvascular complications in diabetes
Authors
Monica Gamez
Hesham E. Elhegni
Sarah Fawaz
Kwan Ho Ho
Neill W. Campbell
David A. Copland
Karen L. Onions
Matthew J. Butler
Elizabeth J. Wasson
Michael Crompton
Raina D. Ramnath
Yan Qiu
Yu Yamaguchi
Kenton P. Arkill
David O. Bates
Jeremy E. Turnbull
Olga V. Zubkova
Gavin I. Welsh
Denize Atan
Simon C. Satchell
Rebecca R. Foster
Publication date
01-12-2024
Publisher
BioMed Central
Published in
Cardiovascular Diabetology / Issue 1/2024
Electronic ISSN: 1475-2840
DOI
https://doi.org/10.1186/s12933-024-02133-1

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