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ISSN (Print): 1381-6128
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Research Article

Soluble Urokinase Plasminogen Activator Receptor Contributes to ANCA-positive IgG-mediated Glomerular Endothelial Activation through TLR4 Pathway

Author(s): Fei Huang, Ranran Xu, Yiru Wang, Yongman Lv and Qingquan Liu*

Volume 29, Issue 2, 2023

Published on: 09 January, 2023

Page: [149 - 161] Pages: 13

DOI: 10.2174/1381612829666221212094441

Price: $65

Abstract

Background: The soluble urokinase plasminogen activator receptor (suPAR), a biomarker of inflammation, has been found to be a potential prognostic factor of renal function progression. Our previous study showed that plasma suPAR levels were significantly associated with disease activity and prognosis in patients with antineutrophil cytoplasmic autoantibody-associated vasculitis (AAV).

Objective: This study aimed to explore whether urokinase plasminogen activator receptor (uPAR) participated in MPO-ANCA-induced glomerular endothelial cell (GEnC) injury, which is one of the most important aspects in the pathogenesis of AAV.

Methods: GEnC activation and injury were analyzed by measuring the mRNA levels of ICAM-1 and VCAM-1. Permeability experiments were performed to detect endothelial monolayer activation in number. The expression of TLR4 was detected. In addition, TLR4 siRNA and TLR4 inhibitors were employed to determine its role. Bioinformatics methods were used for further analysis.

Results: Compared with a single stimulation, uPAR could further increase the expression of ICAM-1 and VCAM-1 mRNA levels, increase endothelial monolayer permeability and impair tight junctions in GEnCs stimulated with MPO-ANCA-positive IgG. The expression of TLR4 was upregulated by uPAR and MPO-ANCApositive IgG stimulation. TLR4 siRNA significantly reduced the expression of ICAM-1 and VCAM-1 mRNA levels induced by uPAR and MPO-ANCA-positive IgG. The TLR4 antagonist significantly downregulated the levels of ICAM-1 mRNA in cells and sICAM-1 in the supernatants of GEnCs treated with uPAR plus MPOANCA- positive IgG. PLAUR is a core gene in bioinformatics analysis.

Conclusion: uPAR protein can enhance the GEnC activation and injury induced by MPO-ANCA-positive IgG through the TLR4 pathway, indicating that suPAR may be involved in the pathogenesis of AAV and that su- PAR might be regarded as a potential therapeutic target.

Keywords: uPAR, antineutrophil cytoplasmic antibody, vasculitis, GEnC, TLR4, bioinformatics analysis.

« Previous Next »
[1]
Jennette JC, Falk RJ. Small-vessel vasculitis. N Engl J Med 1997; 337(21): 1512-23.
[http://dx.doi.org/10.1056/NEJM199711203372106] [PMID: 9366584]
[2]
Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised international chapel hill consensus conference nomenclature of vasculitides. Arthritis Rheum 2013; 65(1): 1-11.
[http://dx.doi.org/10.1002/art.37715] [PMID: 23045170]
[3]
Ntatsaki E, Watts RA, Scott DGI. Epidemiology of ANCA-associated vasculitis. Rheum Dis Clin North Am 2010; 36(3): 447-61.
[http://dx.doi.org/10.1016/j.rdc.2010.04.002] [PMID: 20688243]
[4]
Charles Jennette J. Rapidly progressive crescentic glomerulonephritis. Kidney Int 2003; 63(3): 1164-77.
[http://dx.doi.org/10.1046/j.1523-1755.2003.00843.x] [PMID: 12631105]
[5]
Kallenberg CGM. Pathogenesis of ANCA-associated vasculitis, an update. Clin Rev Allergy Immunol 2011; 41(2): 224-31.
[http://dx.doi.org/10.1007/s12016-011-8258-y] [PMID: 21336557]
[6]
Chen M, Yu F, Zhang Y, Zou WZ, Zhao MH, Wang HY. Characteristics of Chinese patients with Wegener’s granulomatosis with anti-myeloperoxidase autoantibodies. Kidney Int 2005; 68(5): 2225-9.
[http://dx.doi.org/10.1111/j.1523-1755.2005.00679.x] [PMID: 16221222]
[7]
Li ZY, Chang DY, Zhao MH, Chen M. Predictors of treatment resistance and relapse in antineutrophil cytoplasmic antibody-associated vasculitis: A study of 439 cases in a single Chinese center. Arthritis Rheumatol 2014; 66(7): 1920-6.
[http://dx.doi.org/10.1002/art.38621] [PMID: 24623469]
[8]
Nagao T, Matsumura M, Mabuchi A, et al. Up-regulation of adhesion molecule expression in glomerular endothelial cells by anti-myeloperoxidase antibody. Nephrol Dial Transplant 2006; 22(1): 77-87.
[http://dx.doi.org/10.1093/ndt/gfl555] [PMID: 17005520]
[9]
Nagao T, Suzuki K, Utsunomiya K, et al. Direct activation of glomerular endothelial cells by anti-moesin activity of anti-myeloperoxidase antibody. Nephrol Dial Transplant 2011; 26(9): 2752-60.
[http://dx.doi.org/10.1093/ndt/gfr032] [PMID: 21378392]
[10]
Thunø M, Macho B, Eugen-Olsen J. suPAR: The molecular crystal ball. Dis Markers 2009; 27(3-4): 157-72.
[http://dx.doi.org/10.1155/2009/504294] [PMID: 19893210]
[11]
Smith HW, Marshall CJ. Regulation of cell signalling by uPAR. Nat Rev Mol Cell Biol 2010; 11(1): 23-36.
[http://dx.doi.org/10.1038/nrm2821] [PMID: 20027185]
[12]
Backes Y, van der Sluijs KF, Mackie DP, et al. Usefulness of suPAR as a biological marker in patients with systemic inflammation or infection: A systematic review. Intensive Care Med 2012; 38(9): 1418-28.
[http://dx.doi.org/10.1007/s00134-012-2613-1] [PMID: 22706919]
[13]
Pappot H, Høyer-Hansen G, Rønne E, et al. Elevated plasma levels of urokinase plasminogen activator receptor in non-small cell lung cancer patients. Eur J Cancer 1997; 33(6): 867-72.
[http://dx.doi.org/10.1016/S0959-8049(96)00523-0] [PMID: 9291807]
[14]
Sehestedt T, Lyngbæk S, Eugen-Olsen J, et al. Soluble urokinase plasminogen activator receptor is associated with subclinical organ damage and cardiovascular events. Atherosclerosis 2011; 216(1): 237-43.
[http://dx.doi.org/10.1016/j.atherosclerosis.2011.01.049] [PMID: 21354571]
[15]
Sjöwall C, Martinsson K, Cardell K, Ekstedt M, Kechagias S. Soluble urokinase plasminogen activator receptor levels are associated with severity of fibrosis in nonalcoholic fatty liver disease. Transl Res 2015; 165(6): 658-66.
[http://dx.doi.org/10.1016/j.trsl.2014.09.007] [PMID: 25445207]
[16]
Saleem MA. What is the role of soluble urokinase-type plasminogen activator in renal disease? Nephron J 2018; 139(4): 334-41.
[http://dx.doi.org/10.1159/000490118] [PMID: 29909410]
[17]
Wei C, El Hindi S, Li J, et al. Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat Med 2011; 17(8): 952-60.
[http://dx.doi.org/10.1038/nm.2411] [PMID: 21804539]
[18]
Wei C, Möller CC, Altintas MM, et al. Modification of kidney barrier function by the urokinase receptor. Nat Med 2008; 14(1): 55-63.
[http://dx.doi.org/10.1038/nm1696] [PMID: 18084301]
[19]
Hayek SS, Leaf DE, Samman Tahhan A, et al. Soluble urokinase receptor and acute kidney injury. N Engl J Med 2020; 382(5): 416-26.
[http://dx.doi.org/10.1056/NEJMoa1911481] [PMID: 31995687]
[20]
Sudhini YR, Wei C, Reiser J. suPAR: An inflammatory mediator for kidneys. Kidney Dis 2022; 8(4): 265-74.
[http://dx.doi.org/10.1159/000524965] [PMID: 35949208]
[21]
Fujimoto K, Imura J, Atsumi H, et al. Clinical significance of serum and urinary soluble urokinase receptor (suPAR) in primary nephrotic syndrome and MPO-ANCA-associated glomerulonephritis in Japanese. Clin Exp Nephrol 2015; 19(5): 804-14.
[http://dx.doi.org/10.1007/s10157-014-1067-x] [PMID: 25500737]
[22]
Huang F, Li Y, Xu R, Cheng A, Lv Y, Liu Q. The plasma soluble urokinase plasminogen activator receptor is related to disease activity of patients with ANCA-associated vasculitis. Mediators Inflamm 2020; 2020
[23]
Misch EA, Hawn TR. Toll-like receptor polymorphisms and susceptibility to human disease. Clinical science 2008; 114: 347-60.
[http://dx.doi.org/10.1042/CS20070214]
[24]
Holle JU, Windmöller M, Lange C, Gross WL, Herlyn K, Csernok E. Toll-like receptor TLR2 and TLR9 ligation triggers neutrophil activation in granulomatosis with polyangiitis. Rheumatology 2013; 52(7): 1183-9.
[http://dx.doi.org/10.1093/rheumatology/kes415] [PMID: 23407387]
[25]
Summers SA, van der Veen BS, O’Sullivan KM, et al. Intrinsic renal cell and leukocyte-derived TLR4 aggravate experimental anti-MPO glomerulonephritis. Kidney Int 2010; 78(12): 1263-74.
[http://dx.doi.org/10.1038/ki.2010.327] [PMID: 20844472]
[26]
Tadema H, Abdulahad WH, Stegeman CA, Kallenberg CGM, Heeringa P. Increased expression of Toll-like receptors by monocytes and natural killer cells in ANCA-associated vasculitis. PLoS One 2011; 6(9): e24315.
[http://dx.doi.org/10.1371/journal.pone.0024315] [PMID: 21915309]
[27]
O’Sullivan KM, Ford SL, Longano A, Kitching AR, Holdsworth SR. Intrarenal Toll-like receptor 4 and Toll-like receptor 2 expression correlates with injury in antineutrophil cytoplasmic antibody-associated vasculitis. Am J Physiol Renal Physiol 2018; 315(5): F1283-94.
[http://dx.doi.org/10.1152/ajprenal.00040.2018] [PMID: 29923769]
[28]
Wang H, Gou S-J, Zhao M-H, Chen M. The expression of Toll- like receptors 2, 4 and 9 in kidneys of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Clin Exp Immunol 2014; 177(3): 603-10.
[http://dx.doi.org/10.1111/cei.12365] [PMID: 24773611]
[29]
Tinsley JH, Wu MH, Ma W, Taulman AC, Yuan SY. Activated neutrophils induce hyperpermeability and phosphorylation of adherens junction proteins in coronary venular endothelial cells. J Biol Chem 1999; 274(35): 24930-4.
[http://dx.doi.org/10.1074/jbc.274.35.24930] [PMID: 10455168]
[30]
Schreiber A, Rolle S, Peripelittchenko L, et al. Phosphoinositol 3-kinase-γ mediates antineutrophil cytoplasmic autoantibody-induced glomerulonephritis. Kidney Int 2010; 77(2): 118-28.
[http://dx.doi.org/10.1038/ki.2009.420] [PMID: 19907415]
[31]
Liu QQ, Zhou YQ, Liu HQ, et al. Decreased DACH1 expression in glomerulopathy is associated with disease progression and severity. Oncotarget 2016; 7(52): 86547-60.
[http://dx.doi.org/10.18632/oncotarget.13470] [PMID: 27888806]
[32]
Yu G, Wang LG, Han Y, He QY. clusterProfiler: An R package for comparing biological themes among gene clusters. OMICS 2012; 16(5): 284-7.
[http://dx.doi.org/10.1089/omi.2011.0118] [PMID: 22455463]
[33]
Karagkouni D, Paraskevopoulou MD, Chatzopoulos S, et al. DIANA-TarBase v8: A decade-long collection of experimentally supported miRNA-gene interactions. Nucleic Acids Res 2018; 46(D1): D239-45.
[http://dx.doi.org/10.1093/nar/gkx1141] [PMID: 29156006]
[34]
Paraskevopoulou MD, Vlachos IS, Karagkouni D, et al. DIANA-LncBase v2: Indexing microRNA targets on non-coding transcripts. Nucleic Acids Res 2016; 44(D1): D231-8.
[http://dx.doi.org/10.1093/nar/gkv1270] [PMID: 26612864]
[35]
Monach PA, Tomasson G, Specks U, et al. Circulating markers of vascular injury and angiogenesis in antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 2011; 63(12): 3988-97.
[http://dx.doi.org/10.1002/art.30615] [PMID: 21953143]
[36]
Page AV, Liles WC. Biomarkers of endothelial activation/dysfunction in infectious diseases. Virulence 2013; 4(6): 507-16.
[http://dx.doi.org/10.4161/viru.24530] [PMID: 23669075]
[37]
Böhm F, Pernow J. The importance of endothelin-1 for vascular dysfunction in cardiovascular disease. Cardiovasc Res 2007; 76(1): 8-18.
[http://dx.doi.org/10.1016/j.cardiores.2007.06.004] [PMID: 17617392]
[38]
Hartsock A, Nelson WJ. Adherens and tight junctions: Structure, function and connections to the actin cytoskeleton. Biochim Biophys Acta Biomembr 2008; 1778(3): 660-9.
[http://dx.doi.org/10.1016/j.bbamem.2007.07.012] [PMID: 17854762]
[39]
Melincovici CS, Boşca AB, Şuşman S, et al. Vascular endothelial growth factor (VEGF) - key factor in normal and pathological angiogenesis. Rom J Morphol Embryol 2018; 59(2): 455-67.
[PMID: 30173249]
[40]
Hahm E, Wei C, Fernandez I, et al. Bone marrow-derived immature myeloid cells are a main source of circulating suPAR contributing to proteinuric kidney disease. Nat Med 2017; 23(1): 100-6.
[http://dx.doi.org/10.1038/nm.4242] [PMID: 27941791]
[41]
Hayek SS, Sever S, Ko YA, et al. Soluble urokinase receptor and chronic kidney disease. N Engl J Med 2015; 373(20): 1916-25.
[http://dx.doi.org/10.1056/NEJMoa1506362] [PMID: 26539835]
[42]
Han R, Hu S, Qin W, et al. C3a and suPAR drive versican V1 expression in tubular cells of focal segmental glomerulosclerosis. JCI Insight 2019; 4(7): e122912.
[43]
Johnson PA, Alexander HD, McMILLAN SA, Maxwell AP. Up- regulation of the endothelial cell adhesion molecule intercellular adhesion molecule-1 (ICAM-1) by autoantibodies in autoimmune vasculitis. Clin Exp Immunol 2003; 108(2): 234-42.
[http://dx.doi.org/10.1046/j.1365-2249.1997.3741271.x] [PMID: 9158091]
[44]
Huugen D, Xiao H, van Esch A, et al. Aggravation of anti-myeloperoxidase antibody-induced glomerulonephritis by bacterial lipopolysaccharide: role of tumor necrosis factor-alpha. Am J Pathol 2005; 167(1): 47-58.
[http://dx.doi.org/10.1016/S0002-9440(10)62952-5] [PMID: 15972951]
[45]
Halbwachs L, Lesavre P. Endothelium-neutrophil interactions in ANCA-associated diseases. J Am Soc Nephrol 2012; 23(9): 1449-61.
[http://dx.doi.org/10.1681/ASN.2012020119] [PMID: 22942199]
[46]
Haubitz M, Dhaygude A, Woywodt A. Mechanisms and markers of vascular damage in ANCA-associated vasculitis. Autoimmunity 2009; 42(7): 605-14.
[http://dx.doi.org/10.1080/08916930903002503] [PMID: 19863378]
[47]
Pliyev BK, Antonova OA, Menshikov M. Participation of the urokinase-type plasminogen activator receptor (uPAR) in neutrophil transendothelial migration. Mol Immunol 2011; 48(9-10): 1168-77.
[http://dx.doi.org/10.1016/j.molimm.2011.02.011] [PMID: 21470685]
[48]
Kiyan Y, Tkachuk S, Hilfiker-Kleiner D, Haller H, Fuhrman B, Dumler I. oxLDL induces inflammatory responses in vascular smooth muscle cells via urokinase receptor association with CD36 and TLR4. J Mol Cell Cardiol 2014; 66: 72-82.
[http://dx.doi.org/10.1016/j.yjmcc.2013.11.005] [PMID: 24239845]
[49]
Narayanaswamy PB, Tkachuk S, Haller H, Dumler I, Kiyan Y. CHK1 and RAD51 activation after DNA damage is regulated via urokinase receptor/TLR4 signaling. Cell Death Dis 2016; 7(9): e2383.
[http://dx.doi.org/10.1038/cddis.2016.291] [PMID: 27685627]
[50]
Aldabbous L, Abdul-Salam V, McKinnon T, et al. Neutrophil extracellular traps promote angiogenesis. Arterioscler Thromb Vasc Biol 2016; 36(10): 2078-87.
[http://dx.doi.org/10.1161/ATVBAHA.116.307634] [PMID: 27470511]
[51]
Kolaczkowska E, Kubes P. Angiogenic neutrophils: A novel subpopulation paradigm. Blood 2012; 120(23): 4455-7.
[http://dx.doi.org/10.1182/blood-2012-09-457226] [PMID: 23197582]
[52]
Jha AK, Gairola S, Kundu S, et al. Toll-like receptor 4: An attractive therapeutic target for acute kidney injury. Life Sci 2021; 271: 119155.
[http://dx.doi.org/10.1016/j.lfs.2021.119155] [PMID: 33548286]
[53]
Huang RS, Zhou JJ, Feng YY, et al. Pharmacological inhibition of macrophage toll-like receptor 4/nuclear factor-kappa B alleviates rhabdomyolysis-induced acute kidney injury. Chin Med J 2017; 130(18): 2163-9.
[http://dx.doi.org/10.4103/0366-6999.213406] [PMID: 28836571]
[54]
Li J, Tan Y, Wang M, et al. Loganetin protects against rhabdomyolysis-induced acute kidney injury by modulating the toll-like receptor 4 signalling pathway. Br J Pharmacol 2019; 176(8): 1106-21.
[http://dx.doi.org/10.1111/bph.14595] [PMID: 30706443]
[55]
Rossignol P, Ho-Tin-Noé B, Vranckx R, et al. Protease nexin-1 inhibits plasminogen activation-induced apoptosis of adherent cells. J Biol Chem 2004; 279(11): 10346-56.
[http://dx.doi.org/10.1074/jbc.M310964200] [PMID: 14699093]
[56]
Harada M, Habata Y, Hosoya M, et al. N-formylated humanin activates both formyl peptide receptor-like 1 and 2. Biochem Biophys Res Commun 2004; 324(1): 255-61.
[http://dx.doi.org/10.1016/j.bbrc.2004.09.046] [PMID: 15465011]
[57]
Resnati M, Pallavicini I, Wang JM, et al. The fibrinolytic receptor for urokinase activates the G protein-coupled chemotactic receptor FPRL1/LXA4R. Proc Natl Acad Sci USA 2002; 99(3): 1359-64.
[http://dx.doi.org/10.1073/pnas.022652999] [PMID: 11818541]
[58]
Losse J, Zipfel PF, Józsi M. Factor H and factor H-related protein 1 bind to human neutrophils via complement receptor 3, mediate attachment to Candida albicans, and enhance neutrophil antimicrobial activity. J Immunol 2010; 184(2): 912-21.
[http://dx.doi.org/10.4049/jimmunol.0901702] [PMID: 20008295]
[59]
Simon DI, Wei Y, Zhang L, et al. Identification of a urokinase receptor-integrin interaction site. Promiscuous regulator of integrin function. J Biol Chem 2000; 275(14): 10228-34.
[http://dx.doi.org/10.1074/jbc.275.14.10228] [PMID: 10744708]
[60]
Takada YK, Yu J, Fujita M, Saegusa J, Wu CY, Takada Y. Direct binding to integrins and loss of disulfide linkage in interleukin-1β (IL-1β) are involved in the agonistic action of IL-1β. J Biol Chem 2017; 292(49): 20067-75.
[http://dx.doi.org/10.1074/jbc.M117.818302] [PMID: 29030430]
[61]
Amara U, Flierl MA, Rittirsch D, et al. Molecular intercommunication between the complement and coagulation systems. J Immunol 2010; 185(9): 5628-36.
[http://dx.doi.org/10.4049/jimmunol.0903678] [PMID: 20870944]
[62]
Nakazawa D, Masuda S, Tomaru U, Ishizu A. Pathogenesis and therapeutic interventions for ANCA-associated vasculitis. Nat Rev Rheumatol 2019; 15(2): 91-101.
[http://dx.doi.org/10.1038/s41584-018-0145-y] [PMID: 30542206]
[63]
Kiyan Y, Tkachuk S, Rong S, et al. TLR4 response to LPS is reinforced by urokinase receptor. Front Immunol 2020; 11: 573550.
[http://dx.doi.org/10.3389/fimmu.2020.573550] [PMID: 33362762]

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