Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-745bb68f8f-kw2vx Total loading time: 0 Render date: 2025-02-07T00:58:48.349Z Has data issue: false hasContentIssue false

28A - Experimental Models of Glomerulonephritis

from PART VI - ANIMAL MODELS OF INFLAMMATION

Published online by Cambridge University Press:  05 April 2014

By
Aidan Ryan ,
Denise M. Sadlier  and
Catherine Godson
Edited by
Charles N. Serhan ,
Peter A. Ward  and
Derek W. Gilroy
With contributions by
Samir S. Ayoub
Aidan Ryan
Affiliation:
University College Dublin
Denise M. Sadlier
Affiliation:
University College Dublin
Catherine Godson
Affiliation:
University College Dublin
Charles N. Serhan
Affiliation:
Harvard Medical School
Peter A. Ward
Affiliation:
University of Michigan, Ann Arbor
Derek W. Gilroy
Affiliation:
University College London
Get access

Summary

INTRODUCTION

In the human kidney, some 1 million glomeruli filter 180 liters of plasma daily, allowing passage of low-molecular-weight products while restricting the passage of albumin and larger macromolecules. The resulting urine is extensively modified in the renal tubular system, with changes to both composition and volume necessary to maintain extracellular volume and homeostasis. As a consequence of this, immune complexes formed in the circulation are delivered at a high rate to the intraglomerular capillary bed and trapping occurs primarily in the mesangium and or on the subendothelial surface of the capillary wall. In contrast to in vitro models, which are somewhat limited to assessing isolated cell, antibody, and antigen function, or indeed, human biopsy specimens which give a snapshot at a particular clinical stage, in vivo animal models can outline how structure and function changes with initiation, progression, and potential regression within affected organs and the various cellular and humoral factors involved in disease progression. The nephron is the functioning unit of the kidney and the glomerulus is a branching network of capillaries responsible for plasma filtration and the initial step in urine formation. This chapter will review the use of experimental animal models in delineating the pathogenesis of glomerulonephritis (GN). GN at its basic definition is the term used to describe an inflammatory process involving the glomeruli characterized morphologically by an influx of leucocytes and cellular proliferation often accompanied by glomerular capillary wall abnormalities.

Type
Chapter
Information
Fundamentals of Inflammation , pp. 338 - 348
Publisher: Cambridge University Press
Print publication year: 2010

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1. Haraldsson, B., Nystrom, J., and Denn, W.M. 2008. Properties of the glomerular barrier and mechanisms of proteinuria. Physiol Rev 88:451–487.CrossRefGoogle ScholarPubMed
2. D'Amico, G., and Bazzi, C. 2003. Pathophysiology of proteinuria. Kidney Int 63:908–925.CrossRefGoogle ScholarPubMed
3. Pavenstadt, H., Kriz, W., and Kretzler, M. 2003. Cell biology of the glomerular podocyte. Physiol Rev 83:253–307.CrossRefGoogle ScholarPubMed
4. Eremina, V., Cui, S., Gerber, H., et al. 2006. Vascular Endothelial Growth Factor A signaling in podocyte-endothelial compartment is required for mesangial cell migration and survival. J Am Soc Nephrol 17:724–735.CrossRefGoogle ScholarPubMed
5. Nangaku, M., and Couser, W.G. 2005. Mechanisms of immune-deposit formation and the mediation of immune renal injury. Clin Exp Nephrol 9:183–191.CrossRefGoogle ScholarPubMed
6. Horster, M.F., Braun, G.S., and Huber, S.M. 1999. Embryonic renal epithelia: induction, nephrogenesis and cell differentiation. Physiol Rev 79:1157–1191.CrossRefGoogle ScholarPubMed
7. Khan, S.R. 1997. Animal models of kidney stone formation: an analysis. World J Urol 15:236–243.CrossRefGoogle ScholarPubMed
8. Dressler, G.R. 2006. The cellular basis of kidney development. Annu Rev Cell Dev Biol 22:509–529.CrossRefGoogle ScholarPubMed
9. Singh, S.R., and Hou, S.X. 2008. Lessons learned about adult kidney stem cells from the malpighian tubules of Drosophila. J Am Soc Nephrol 19:660–666.CrossRefGoogle ScholarPubMed
10. Babinet, C. 2000. Transgenic mice: an irreplaceable Tool for the study of mammalian development and biology. J Am Soc Nephrol 11:s88–s94.Google Scholar
11. Wiznerowicz, M., Szulc, J., and Trono, D. 2006. Tuning silence: conditional systems for RNA interference. Nat Methods 3(9):682–688.CrossRefGoogle ScholarPubMed
12. Bhindi, R., Fahmy, R.G., Lowe, H.C., et al. 2007. Brothers in arms; DNA enzymes, short interfering RNA, and the emerging wave of small-molecule nucleic acid-based gene-silencing strategies. Am J Pathol 171(4): 1079–1088.Google ScholarPubMed
13. Moroy, T., and Heyd, F. 2008. The impact of alternative splicing in vivo: mouse models show the way. RNA 13:1155–1171.Google Scholar
14. Chadban, S.J., and Atkins, R.C. 2005. Glomerulonephritis. Lancet 365:1797–1806.CrossRefGoogle ScholarPubMed
15. Taniguchi, H., Kojima, R., Sade, H., Furuya, M., Inomata, N., and Ito, M. 2007. Involvement of MCP-1 in tubulointerstitial fibrosis through massive proteinuria in anti-GBM nephritis induced in WKY rats. J Clin Immunol 27(4):409–429.CrossRefGoogle ScholarPubMed
16. Mantovani, A., Sica, A., and Locati, M. 2007. New vistas on macrophage differentiation and activation. Eur J Immunol 37:14–16.CrossRefGoogle ScholarPubMed
17. Kurts, C., Heymann, F., Lukacs-Kornek, V., Boor, P., and Floege, J. 2007. Role of T cells and dendritic cells in glomerular immunopathology. Semin Immunopathol 29(4):317–335.CrossRefGoogle ScholarPubMed
18. Tipping, P.G., and Kitching, A.R. 2005. Glomerulonephritis, Th1 and Th2: what's new?Clin Exp Immunol 142:207–215.CrossRefGoogle ScholarPubMed
19. Tipping, P.G., and Holdsworth, S.R. 2007. Cytokines in glomerulonephritis. Semin Nephrol 27(3):275–285.CrossRefGoogle ScholarPubMed
20. Kado, T., Kohda, T., Okada, S., et al. 2006. Immunohistochemical characterization of glomerular inflammatory cells and expression of adhesion molecules in anti-glomerular basement membrane glom-erulonephritis induced in WKY rats with monoclonal anti-GBM antibodies of different subclasses. Pathol Int 56(2):55–61.CrossRefGoogle ScholarPubMed
21. Schreiber, A., Xiao, H., Falk, R.J., and Jeanette, J.C. 2006. Bone-marrow derived cells are sufficient and necessary targets to mediate glomerulonephritis and vasculitis induced by antimyeloperoxidase antibodies. J Am Soc Nephrol 17:3355–3364.CrossRefGoogle Scholar
22. Ruth, A.J., Kitching, A.R., Kwan, R.Y., et al. 2006. Anti-neutrophil cytoplasmic antibodies and effector CD4+ cells play nonredundant roles in anti-myeloperoxidase crescentic glomerulonephritis. J Am Soc Nephrol 17:1940–1949.CrossRefGoogle ScholarPubMed
23. Bao, L., and Quigg, R.J. 2007. Complement in lupus nephritis: the good, the bad, and the unknown. Semin Nephrol 27(1):69–80.CrossRefGoogle ScholarPubMed
24. Clynes, R., Durnitru, C., and Ravetch, J.V. 1998. Uncoupling of immune complex formation and kidney damage in autoimmune glomerulonephritis. Science 279:1052–1054.CrossRefGoogle ScholarPubMed
25. Xiao, H., Heeringa, P., Hu, P., et al. 2002. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vascultis in mice. J Clin Invest 110:955–963.CrossRefGoogle Scholar
26. Timoshanko, J.R., Sedgwick, J.D., Holdsworth, S.R., and Tipping, P.G. 2003. Intrinsic renal cells are the major source of tumor necrosis factor contributing to renal injury in murine crescentic glomerulonephritis. J Am Soc Nephrol 14(7):1785–1793.CrossRefGoogle ScholarPubMed
27. Liu, Y. 2006. Renal fibrosis: new insights into the pathogenesis and therapeutics. Kidney Int 69:213–217.CrossRefGoogle ScholarPubMed
28. Yang, J., Zhang, X., Li, Y., et al. 2003. Downregulation of Smad transcriptional corepressors SnoN and Ski in the fibrotic kidney: an amplification mechanism for TGF-beta 1 signaling. J Am Soc Nephrol 14:3167–3177.CrossRefGoogle Scholar
29. Shimizu, M., Shuji, K., Urushihara, M., et al. 2006. Role of integrin-linked kinase in epithelial-mesenchymal transition in crescent formation of experimental glom-erulonephritis. Nephrol Dial Transplant 21:2380–2390.CrossRefGoogle Scholar
30. Czyzyk, J. 2006. The role of Toll-like receptors in the pathogenesis of renal disease. Semin Nephrol 26:167–172.CrossRefGoogle ScholarPubMed
31. Barrat, F.J., Meeker, T., Chan, J.H., Guiducci, C., and Coffman, R.L. 2007. Treatment of lupus-prone mice with a dual inhibitor of TLR7 and TLR9 leads to reduction of autoantibody production and amelioration of disease symptoms. Eur J Immunol 37(12):3582–3586.CrossRefGoogle ScholarPubMed
32. Banas, M.C., Banas, B., Hudkins, K.L., et al. 2008. TLR4 links podocytes with the innate immune system to mediate glomerular injury. J Am Soc Nephrol. 19(4):704–713.CrossRefGoogle ScholarPubMed
33. Chen, C.A., Hwang, J.C., Guh, J.Y., Chang, J.M., Lai, Y.H., and Chen, H.C. 2006. Reduced podocyte expression of alpha3beta1 integrins and podocyte depletion in patients with primary focal segmental glomerulosclerosis and chronic PAN-treated rats. J Lab Clin Med 147:74–82.CrossRefGoogle ScholarPubMed
34. Kalluri, R., and Cosgrave, D. 2000. Assembly of type 4 collagen. Insights from alpha3 collagen-deficient mice. J Biol Chem 275:12719–12724.CrossRefGoogle Scholar
35. Krestila, M., Lenkkeri, U., Mannikko, M., et al. 1998. Positionally cloned gene for a novel glomerular proteinnephrin-is mutated in congenital nephritic syndrome. Mol Cell 1:575–582.Google Scholar
36. Michaud, J.R., and Kennedy, C.J. 2007. The podocyte in health and disease: insights form the mouse. Clin Sci 112:325–335.CrossRefGoogle ScholarPubMed
37. Petermann, A., and Floege, J. 2007. Podocyte damage resulting in podocyturia: a potential diagnostic marker to assess glomerular disease activity. Nephron Clin Pract 106:c61–c66.CrossRefGoogle ScholarPubMed
38. Kriz, W. 2002. Podocyte is the major culprit accounting for the progression of chronic renal disease. Microsc Res Tech 15:189–195.Google Scholar
39. Wiggins, R.C. 2007. The spectrum of podocytopa-thies: a unifying view of glomerular diseases. Kidney Int 71:1205–1214.CrossRefGoogle ScholarPubMed
40. Levidiotis, V., and Power, D.A. 2005. New insights into the molecular biology of the glomerular filtration barrier and associated disease. Nephrology 10:157–166.CrossRefGoogle ScholarPubMed
41. Cosgrove, D., Meehan, D.T., Grunkemeyer, J.A., et al. 1996. Collagen COL4A3 knockout: a mouse model for autosomal Alport's syndrome. Genes Dev 10:2981–2992.CrossRefGoogle Scholar
42. Ruotsalainen, V., Ljungberg, P., Wartiovaara, J., et al. 1999. Nephrin is specifically located at the slit diaphragm of glomerular podocytes. Proc Natl Acad Sci USA 96:7962–7967.CrossRefGoogle ScholarPubMed
43. Rantanen, M., Palmen, T., Patari, A., et al. 2002. Nephrin TRAP mice lack slit diaphragms and show fibrotic glomeruli and cystic tubular lesions. J Am Soc Nephrol 13:1586–1594.CrossRefGoogle ScholarPubMed
44. Roselli, S., Heidet, L., Sich, M., et al. 2004. Early glomerular filtration defect and severe renal disease in podocin-deficient mice. Mol Cell Biol 24:55–560.CrossRefGoogle ScholarPubMed
45. Deen, W.M., Lazzara, M.J., and Myers, B.D. 2001. Structural determinants of glomerular permeability. Am J Physiol 281:F579–F596.Google ScholarPubMed
46. Ballermann, B.J. 2007. Contribution of the endothelium to the glomerular permaselectivity barrier in health and disease. Nephron Physiol 106:19–25.CrossRefGoogle ScholarPubMed
47. Kriz, W., and Lehir, M. 2005. Pathways to nephron loss starting from glomerular diseases – insights form animal models. Kidney Int 67:404–419.CrossRefGoogle Scholar
48. Tryggvason, K., and Petersson, E. 2003. Causes and consequences of proteinuria: the kidney filtration barrier and progressive renal failure. J Intern Med 254:216–224.CrossRefGoogle ScholarPubMed
49. Kaissling, B., and Le Hir, M. 2008. The renal cortical interstitium; morphological and functional aspects. Histochem Cell Biol 130:247–262.CrossRefGoogle ScholarPubMed
50. Bajema, I., Hagen, E., Hermans, J., et al. 1999. Kidney biopsy as a predictor for renal outcome in ANCA- associated necrotising glomerulonephritis. Kidney Int 56:1751–1758.CrossRefGoogle Scholar
51. Couser, W.G. 1988. Rapidly progressive glomerulonephritis: classification, pathogenetic mechanisms and therapy. Am J Kidney Disease 11:449–464.CrossRefGoogle ScholarPubMed
52. Kluth, D.C., and Rees, A.J. 1999. Antiglomerular basement membrane disease. J Am Soc Nephrol 10:24–46.Google Scholar
53. Pusey, C.D., Holland, M.J., Cashman, S.J., et al. 1991. Experimental autoimmune glomerulonephritis induced by homologous and isologous glomerular basement membrane in Brown Norway rats. Nephrol Dial Transplant 6:457–465.CrossRefGoogle ScholarPubMed
54. Reynolds, J., Cook, P.R., Ryan, J.J., et al. 2002. Segregation of experimental autoimmune glomerulonephritis as a complex genetic trait and exclusion of Col4a3 as a candidate gene. Exp Nephrol 10:402–407.CrossRefGoogle ScholarPubMed
55. Wu, J., Hicks, J., Borillo, J., Glass, W.F. II and Lou, Y.H. 2002. CD4(+) T cells specific to a glomerular basement membrane antigen mediate glomerulonephritis. J Clin Invest 109:517–524.CrossRefGoogle ScholarPubMed
56. Rops, A.L., Gotte, M., Baselmans, M.H., et al. 2007. Syndecan-1 deficiency aggravates antiglomerular basement membrane nephritis. Kidney Int 72(10):1204–1215.CrossRefGoogle Scholar
57. Arends, J., Wu, J., Borillo, J., et al. 2006. T cell epitope mimicry in antiglomerular basement membrane disease. J Immunol 176(2):1252–1258.CrossRefGoogle ScholarPubMed
58. Hochberg, M.C. 1997. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 40:1725.CrossRefGoogle ScholarPubMed
59. D'Cruz, D.P., Khamashta, M.A., and Hughes, G.R. 2007. Systemic lupus erythematosus. Lancet 369(9561):587–596.CrossRefGoogle ScholarPubMed
60. Kirching, A.R., Holdsworth, S.R., and Tipping, P.G. 2000. Crescentic glomerulonephritis-a manifestation of a nephritogenic Th1 response?Histol Histopathol 15:993–1003.Google Scholar
61. Karkar, A.M., Smith, J., and Pusey, C.D. 2001. Prevention and treatment of experimental crescentic glomerulonephritis by blocking tumor necrosis factor alpha. Nephrol Dial Transplant 16:518–524.CrossRefGoogle Scholar
62. Hicks, J., and Bullard, D.C. 2006. Review of autoimmune (lupus-like) glomerulonephritis in murine models. Ultrastruct Pathol 2006; 30:5, 345–359.CrossRefGoogle ScholarPubMed
63. Theofilopoulos, A.N. 1998. Effector and predisposing genes in murine lupus. Lupus 7:575–584.CrossRefGoogle ScholarPubMed
64. Graham, D.S.C., and Vyse, T.J. 2004. The candidate gene approach: have murine models informed the study of human SLE?Clin Exp Immunol 137:1–7.Google Scholar
65. Kiely, P.D., Pecht, I., and Oliveira, D.B. 1997. Mercuric chloride-induced vasculitis in the Brown Norway rat: alpha beta T cell-dependent and independent phases: role of the mast cell. J Immunol 159: 5100–5106.Google Scholar
66. Couser, W.G., and Nangaku, M. 2006. Cellular and molecular biology of membranous nephropathy. J Nephrol 19(6):699–705.Google ScholarPubMed
67. Jefferson, J.A., and Johnson, R.J. 1999. Experimental mesangial proliferative glomerulonephritis (the anti-Thy-1.1 model). J Nephrol 12(5):297–307.Google Scholar
68. Pickering, M.C., and Cook, H.T. 2008. Translational mini-review series on complement factor H: renal diseases associated with complement factor H: novel insights from human and animals. Clin Exp Immunol 151:210–230.CrossRefGoogle ScholarPubMed
69. Cosgrove, D., Kalluri, R., Miner, J.H., Segal, Y., and Borza, D.B. 2007. Choosing a mouse model to study the molecular pathobiology of Alport's glomerulonephritis. Kidney Int 71(7):615–618.CrossRefGoogle Scholar
70. Suzuki, H., Suzuki, Y., Aizawa, M., et al. 2007. Th1 polarization in murine IgA nephropathy directed by bone marrow-derived cells. Kidney Int 72:319–327.CrossRefGoogle ScholarPubMed
71. Fogo, A.B. 2003. Animal models of FSGS: lessons for pathogenesis and treatment. Semin Nephrol 23(2):161–171.CrossRefGoogle ScholarPubMed
72. Reidy, K., and Kaskel, F.J. 2007. Pathophysiology of focal segmental glomerulosclerosis. Pediatr Nephrol 22(3):350–354.CrossRefGoogle ScholarPubMed
73. Hiramatsu, N., Hiromura, K., Shigehara, T., et al. 2007. Angiotensin 2 type 1 receptor blockade inhibits the development and progression of HIV-associated nephropathy in a mouse model. J Am Soc Nephrol 18(2):515–527.CrossRefGoogle ScholarPubMed
Dressler, G.R. 2006. The cellular basis of kidney development. Annu Rev Cell Dev Biol 22:509–529.CrossRefGoogle ScholarPubMed
Haraldsson, B., Nystrom, J., and Denn, W.M. 2008. Properties of the glomerular barrier and mechanisms of proteinuria. Physiol Rev 88:451–487.CrossRefGoogle ScholarPubMed
Nangaku, M., and Couser, W.G. 2005. Mechanisms of immune-deposit formation and the mediation of immune renal injury. Clin Exp Nephrol 9:183–191.CrossRefGoogle ScholarPubMed
Tipping, P.G., and Holdsworth, S.R. 2007. Cytokines in glomerulonephritis. Semin Nephrol 27(3):275–285.CrossRefGoogle ScholarPubMed

Save book to Kindle

To save this book to your Kindle, first ensure [email protected] is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×