Background: The high IgA (HIGA) strain of ddY mice represents an inbred model of IgA nephropathy that shows mesangioproliferative glomerulonephritis with mesangial IgA deposition. In this study, aggravation of glomerulonephritis in HIGA mice through lipopolysaccharide (LPS)-triggered activation of coagulation was investigated. Methods: Twelve-week-old HIGA and BALB/c mice were intraperitoneally injected with LPS twice at an interval of 3 days, and kidney specimens were collected 7 days after the second LPS injection. In an intervention experiment, the factor Xa inhibitor danaparoid was injected intraperitoneally every day for 7 days after the first LPS injection. Results: LPS injection induced macrophage infiltration and cellular proliferation in the mesangium together with fibrin deposition and monocyte chemoattractant protein 1 mRNA expression, as well as antigen deposition of tissue factor, factor V, factor X, and protease-activated receptor 2. These phenomena were obvious in HIGA mice when compared to BALB/c mice. Interestingly, toll-like receptor 4 was intensely expressed in HIGA mice before LPS injection and subsequently decreased. Danaparoid treatment significantly ameliorated proteinuria, cellular proliferation, and fibrin deposition. Conclusions: The present data suggest that tissue factor and factor V induction by LPS may in part accelerate mesangioproliferative glomerulonephritis through activation of factor X and downstream proinflammatory and procoagulant mechanisms.

Keywords:
Factor X, Factor V, Protease-activated receptor 2, Toll-like receptor 4
1.
Mestecky J, Tomana M, Crowley-Nowick PA, Moldoveanu Z, Julian BA, Jackson S: Defective galactosylation and clearance of IgA1 molecules as a possible etiopathogenic factor in IgA nephropathy. Contrib Nephrol 1993;104:172–182.
2.
Monteiro RC, Halbwachs-Mecarelli L, Roque-Barreira MC, Noel LH, Berger J, Lesavre P: Charge and size of mesangial IgA in IgA nephropathy. Kidney Int 1985;28:666–671.
3.
Chauveau D, Droz D: Follow-up evaluation of the first patients with IgA nephropathy described at Necker Hospital; in Béné MC, Faure G, Kesseler M (eds): IgA Nephropathy. The 25th Year. Contrib Nephrol. Basel, Karger, 1993, pp 1–5.
4.
Falk RJ, Jennette JC, Nachman PH: Primary glomerular disease; in Brenner BM (ed): Brenner and Rector’s the Kidney, ed 6. Philadelphia, WB Saunders, 2000, vol 2, pp 1263–1349.
5.
Creagh EM, O’Neill LA: TLRs, NLRs and RLRs: a trinity of pathogen sensors that co-operate in innate immunity. Trends Immunol 2006;27:352–357.
6.
Hoshino K, Takeuchi O, Kawai T, Sanjo H, Ogawa T, Takeda Y, Takeda K, Akira S: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J Immunol 1999;162:3749–3752.
7.
Wiggins RC, Njoku N, Sedor JR: Tissue factor production by cultured rat mesangial cells. Stimulation by TNF alpha and lipopolysaccharide. Kidney Int 1990;37:1281–1285.
8.
Anders H-J: Innate pathogen recognition in the kidney: toll-like receptors, NOD-like receptors, and RIG-like helicases. Kidney Int 2007;72:1051–1056.
9.
Patole PS, Pawar RD, Lech M, Zecher D, Schmidt H, Segerer S, Ellwart A, Henger A, Kretzler M, Anders HJ: Expression and regulation of Toll-like receptors in lupus-like immune complex glomerulonephritis of MRL-Fas(lpr) mice. Nephrol Dial Transplant 2006;21:3062–3073.
10.
Brown HJ, Lock HR, Wolfs TG, Buurman WA, Sacks SH, Robson MG: Toll-like receptor 4 ligation on intrinsic renal cells contributes to the induction of antibody-mediated glomerulonephritis via CXCL1 and CXCL2. J Am Soc Nephrol 2007;18:1732–1739.
11.
Pawar RD, Patole PS, Ellwart A, Lech M, Segerer S, Schlondorff D, Anders HJ: Ligands to nucleic acid-specific toll-like receptors and the onset of lupus nephritis. J Am Soc Nephrol 2006;17:3365–3373.
12.
Imai H, Nakamoto Y, Asakura K, Miki K, Yasuda T, Miura AB: Spontaneous glomerular IgA deposition in ddY mice: an animal model of IgA nephritis. Kidney Int 1985;27:756–761.
13.
Miyawaki S, Muso E, Takeuchi E, Matsushima H, Shibata Y, Sasayama S, Yoshida H: Selective breeding for high serum IgA levels from noninbred ddY mice: isolation of a strain with an early onset of glomerular IgA deposition. Nephron 1997;76:201–207.
14.
Muso E, Yoshida H, Takeuchi E, Yashiro M, Matsushima H, Oyama A, Suyama K, Kawamura T, Kamata T, Miyawaki S, Izui S, Sasayama S: Enhanced production of glomerular extracellular matrix in a new mouse strain of high serum IgA ddY mice. Kidney Int 1996;50:1946–1957.
15.
Oida E, Nogaki F, Kobayashi I, Kamata T, Ono T, Miyawaki S, Serikawa T, Yoshida H, Kita T, Muso E: Quantitative trait loci (QTL) analysis reveals a close linkage between the hinge region and trimeric IgA dominancy in a high IgA strain (HIGA) of ddY mice. Eur J Immunol 2004;34:2200–2208.
16.
Nogaki F, Oida E, Kamata T, Kobayashi I, Nomura K, Suyama K, Tahara S, Ono T, Miyawaki S, Serikawa T, Yoshida H, Kita T, Muso E: Chromosomal mapping of hyperserum IgA and glomerular IgA deposition in a high IgA (HIGA) strain of ddY mice. Kidney Int 2005;68:2517–2525.
17.
Ono T, Muso E, Suyama K, Oyama A, Matsushima H, Yashiro M, Kuwahara T, Yoshida H, Kanatsu K, Sasayama S: Intraglomerular deposition of intact cross-linked fibrin in IgA nephropathy and Henoch-Schönlein purpura nephritis. Nephron 1996;74:522–528.
18.
Tipping PG, Dowling JP, Holdsworth SR: Glomerular procoagulant activity in human proliferative glomerulonephritis. J Clin Invest 1988;81:119–125.
19.
Tipping PG, Erlich JH, Apostolopoulos J, Mackman N, Loskutoff D, Holdsworth SR: Glomerular tissue factor expression in crescentic glomerulonephritis. Correlations between antigen, activity, and mRNA. Am J Pathol 1995;147:1736–1748.
20.
Kane WH, Ichinose A, Hagen FS, Davie EW: Cloning of cDNAs coding for the heavy chain region and connecting region of human factor V, a blood coagulation factor with four types of internal repeats. Biochemistry 1987;26:6508–6514.
21.
Mann KG, Jenny RJ, Krishnaswamy S: Cofactor proteins in the assembly and expression of blood clotting enzyme complexes. Annu Rev Biochem 1988;57:915–956.
22.
Liu N, Ono T, Suyama K, Nogaki F, Shirakawa K, Maeda M, Kawamura T, Kamata T, Oyama A, Muso E, Sasayama S: Mesangial factor V expression colocalized with fibrin deposition in IgA nephropathy. Kidney Int 2000;58:598–606.
23.
Monno R, Grandaliano G, Faccio R, Ranieri E, Martino C, Gesualdo L, Schena FP: Activated coagulation factor X: a novel mitogenic stimulus for human mesangial cells. J Am Soc Nephrol 2001;12:891–899.
24.
Nomura K, Liu N, Nagai K, Hasegawa T, Kobayashi I, Nogaki F, Tanaka M, Arai H, Fukatsu A, Kita T, Ono T: Roles of coagulation pathway and factor Xa in rat mesangioproliferative glomerulonephritis. Lab Invest 2007;87:150–160.
25.
Tanaka M, Arai H, Liu N, Nogaki F, Nomura K, Kasuno K, Oida E, Kita T, Ono T: Role of coagulation factor Xa and protease-activated receptor 2 in human mesangial cell proliferation. Kidney Int 2005;67:2123–2133.
26.
Banas MC, Banas B, Hudkins KL, Wietecha TA, Iyoda M, Bock E, Hauser P, Pippin JW, Shankland SJ, Smith KD, Stoelcker B, Liu G, Gröne HJ, Krämer BK, Alpers CE: TLR4 links podocytes with the innate immune system to mediate glomerular injury. J Am Soc Nephrol 2008;19:704–713.
27.
Suzuki H, Suzuki Y, Narita I, Aizawa M, Kihara M, Yamanaka T, Kanou T, Tsukaguchi H, Novak J, Horikoshi S, Tomino Y: Toll-like receptor 9 affects severity of IgA nephropathy. J Am Soc Nephrol 2008;19:2384–2395.
28.
Hewitson TD, Mookerjee I, Masterson R, Zhao C, Tregear GW, Becker GJ, Samuel CS: Endogenous relaxin is a naturally occurring modulator of experimental renal tubulointerstitial fibrosis. Endocrinology 2007;148:660–669.
29.
Lan RS, Stewart GA, Goldie RG, Henry PJ: Altered expression and in vivo lung function of protease-activated receptors during influenza A virus infection in mice. Am J Physiol Lung Cell Mol Physiol 2004;286:L388–L398.
30.
Fransson M, Adner M, Erjefalt J, Jansson L, Uddman R, Cardell LO: Up-regulation of Toll-like receptors 2, 3 and 4 in allergic rhinitis. Respir Res 2005;6:100.
31.
Aihara K, Azuma H, Akaike M, Ikeda Y, Yamashita M, Sudo T, Hayashi H, Yamada Y, Endoh F, Fujimura M, Yoshida T, Yamaguchi H, Hashizume S, Kato M, Yoshimura K, Yamamoto Y, Kato S, Matsumoto T: Disruption of nuclear vitamin D receptor gene causes enhanced thrombogenicity in mice. J Biol Chem 2004;279:35798–35802.
32.
Kitagawa K, Wada T, Furuichi K, Hashimoto H, Ishiwata Y, Asano M, Takeya M, Kuziel WA, Matsushima K, Mukaida N, Yokoyama H: Blockade of CCR2 ameliorates progressive fibrosis in kidney. Am J Pathol 2004;165:237–246.
33.
Dan Q, Wong R, Chung SK, Chung SS, Lam KS: Interaction between the polyol pathway and non-enzymatic glycation on aortic smooth muscle cell migration and monocyte adhesion. Life Sci 2004;76:445–459.
34.
Vassalli P, McCluskey RT: The pathogenetic role of coagulation process in glomerular diseases of immunological origin. Adv Nephrol Necker Hosp 1971;1:47–63.
35.
Ono T, Liu N, Kasuno K, Kusano H, Nogaki F, Kamata T, Suyama K, Muso E, Sasayama S: Coagulation process proceeds on cultured human mesangial cells via expression of factor V. Kidney Int 2001;60:1009–1017.
36.
Liu N, Mori N, Iehara N, Uemura K, Fukatsu A, Kita T, Matsuda M, Ono T: Soluble fibrin formation in the mesangial area of IgA nephropathy. Clin Exp Nephrol 2007;11:71–76.
37.
Hutter R, Valdiviezo C, Sauter BV, Savontaus M, Chereshnev I, Carrick FE, Bauriedel G, Lüderitz B, Fallon JT, Fuster V, Badimon JJ: Caspase-3 and tissue factor expression in lipid-rich plaque macrophages: evidence for apoptosis as link between inflammation and atherothrombosis. Circulation 2004;109:2001–2008.
38.
Fu Y, Xie C, Yan M, Li Q, Joh JW, Lu C, Mohan C: The lipopolysaccharide-triggered mesangial transcriptome: evaluating the role of interferon regulatory factor-1. Kidney Int 2005;67:1350–1361.
39.
Wright DJ, Morris DP, Stafford DW: Vitamin K-dependent gamma-glutamyl carboxylase; in High KA, Roberts HR (eds): Molecular Basis of Thrombosis and Hemostasis. New York, Marcel Dekker, 1995, pp 309–329.
40.
Senden NH, Jeunhomme TM, Heemskerk JW, Wagenvoord R, van’t Veer C, Hemker HC, Buurman WA: Factor Xa induces cytokine production and expression of adhesion molecules by human umbilical vein endothelial cells. J Immunol 1998;161:4318–4324.
41.
Shultz PJ, Knauss TC, Mene P, Abboud HE: Mitogenic signals for thrombin in mesangial cells: regulation of phospholipase C and PDGF genes. Am J Physiol 1989;257:F366–F374.
42.
Macfarlane SR, Seatter MJ, Kanke T, Hunter GD, Plevin R: Proteinase-activated receptors. Pharmacol Rev 2001;53:245–282.
43.
Ossovskaya VS, Bunnett NW: Protease-activated receptors: contribution to physiology and disease. Physiol Rev 2004;84:579–621.
44.
Coughlin SR: Thrombin signalling and protease-activated receptors. Nature 2000;407:258–264.
45.
Dugina TN, Kiseleva EV, Chistov IV, Umarova BA, Strukova SM: Receptors of the PAR family as a link between blood coagulation and inflammation. Biochemistry (Mosc) 2002;67:65–74.
46.
Grand RJ, Turnell AS, Grabham PW: Cellular consequences of thrombin-receptor activation. Biochem J 1996;313:353–368.
47.
Camerer E, Kataoka H, Kahn M, Lease K, Coughlin SR: Genetic evidence that protease-activated receptors mediate factor Xa signaling in endothelial cells. J Biol Chem 2002;277:16081–16087.
48.
Kawaguchi S, Tanaka H, Hoshino K, Katsumata Y, Masuda Y, Ishizaki M, Yamanaka N, Masugi Y: Suppression of glomerular IgA deposition in ddY mice through periodic injections of lipopolysaccharides. Clin Immunol Immunopathol 1988;48:362–370.
49.
Kobayashi I, Nogaki F, Kusano H, Ono T, Miyawaki S, Yoshida H, Muso E: Interleukin-12 alters the physicochemical characteristics of serum and glomerular IgA and modifies glycosylation in a ddY mouse strain having high IgA levels. Nephrol Dial Transplant 2002;17:2108–2116.
50.
Wei C, Möller CC, Altintas MM, Li J, Schwarz K, Zacchigna S, Xie L, Henger A, Schmid H, Rastaldi MP, Cowan P, Kretzler M, Parrilla R, Bendayan M, Gupta V, Nikolic B, Kalluri R, Carmeliet P, Mundel P, Reiser J: Modification of kidney barrier function by the urokinase receptor. Nat Med 2008;14:55–63.
51.
Acostamadiedo JM, Iyer UG, Owen J: Danaparoid sodium. Expert Opin Pharmacother 2000;1:803–814.
52.
Hagiwara S, Iwasaka H, Hidaka S, Hishiyama S, Noguchi T: Danaparoid sodium inhibits systemic inflammation and prevents endotoxin-induced acute lung injury in rats. Crit Care 2008;12:R43.
53.
Nomura F, Akashi S, Sakao Y, Sato S, Kawai T, Matsumoto M, Nakanishi K, Kimoto M, Miyake K, Takeda K, Akira S: Cutting edge: endotoxin tolerance in mouse peritoneal macrophages correlates with down-regulation of surface toll-like receptor 4 expression. J Immunol 2000;164:3476–3479.
54.
Takahashi H, Ebihara S, Okazaki T, Asada M, Sasaki H, Yamaya M: A comparison of the effects of unfractionated heparin, dalteparin and danaparoid on vascular endothelial growth factor-induced tumour angiogenesis and heparanase activity. Br J Pharmacol 2005;146:333–343.
55.
Meuleman DG, Hobbelen PM, van Dedem G, Moelker HC: A novel anti-thrombotic heparinoid (Org 10172) devoid of bleeding inducing capacity: a survey of its pharmacological properties in experimental animal models. Thromb Res 1982;27:353–363.
© 2009 S. Karger AG, Basel
2009
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.