Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1995 Dec;96(6):2809–2819. doi: 10.1172/JCI118351

Basic fibroblast growth factor augments podocyte injury and induces glomerulosclerosis in rats with experimental membranous nephropathy.

J Floege 1, W Kriz 1, M Schulze 1, M Susani 1, D Kerjaschki 1, A Mooney 1, W G Couser 1, K M Koch 1
PMCID: PMC185991  PMID: 8675651

Abstract

Podocyte injury is believed to contribute to glomerulosclerosis in membranous nephropathy. To identify the factors involved, we investigated the effects of basic fibroblast growth factor (bFGF), a cytokine produced by podocytes, on rats with membranous nephropathy (passive Heymann nephritis [PHN]). All rats received a daily i.v. bolus of 10 microg bFGF or vehicle from days 3-8 after PHN induction. In proteinuric PHN rats on day 8, bFGF injections further increased proteinuria. Podocytes of bFGF-injected PHN rats showed dramatic increases in mitoses, pseudocyst formation, foot process retraction, focal detachment from the glomerular basement membrane, and desmin expression. bFGF injections in PHN rats did not alter antibody or complement deposition or glomerular leukocyte influx. bFGF-injected PHN rats developed increased glomerulosclerosis when compared with control PHN rats. Also, bFGF induced proteinuria and podocyte damage in rats injected with 10% of the regular PHN-serum dose. None of these changes occurred in bFGF-injected normal rats, complement-depleted PHN rats or rats injected with 5% of the regular PHN serum dose. These divergent bFGF effects were explained in part by upregulated glomerular bFGF receptor expression, induced by PHN serum. Thus, bFGF can augment podocyte damage, resulting in increased glomerular protein permeability and accelerated glomerulosclerosis. This bFGF action is confined to previously injured podocytes. Release of bFGF from glomerular sources (including podocytes themselves) during injury may represent an important mechanism by which podocyte damage is enhanced or becomes self sustained.

Full text

PDF
2809

Images in this article

2812Image
on p.2812
2812Image
on p.2812
2812Image
on p.2812
2812Image
on p.2812
2813Image
on p.2813
2814Image
on p.2814
2814Image
on p.2814
2817Image
on p.2817
2818Image
on p.2818

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adler S., Striker L. J., Striker G. E., Perkinson D. T., Hibbert J., Couser W. G. Studies of progressive glomerular sclerosis in the rat. Am J Pathol. 1986 Jun;123(3):553–562. [PMC free article] [PubMed] [Google Scholar]
  2. Alousi M. A., Post R. S., Heymann W. Experimental autoimmune nephrosis in rats. Morphogenesis of the glomerular lesion: immunohistochemical and electron microscopic studies. Am J Pathol. 1969 Jan;54(1):47–71. [PMC free article] [PubMed] [Google Scholar]
  3. Baker A. J., Mooney A., Hughes J., Lombardi D., Johnson R. J., Savill J. Mesangial cell apoptosis: the major mechanism for resolution of glomerular hypercellularity in experimental mesangial proliferative nephritis. J Clin Invest. 1994 Nov;94(5):2105–2116. doi: 10.1172/JCI117565. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Benzaquen L. R., Nicholson-Weller A., Halperin J. A. Terminal complement proteins C5b-9 release basic fibroblast growth factor and platelet-derived growth factor from endothelial cells. J Exp Med. 1994 Mar 1;179(3):985–992. doi: 10.1084/jem.179.3.985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Camussi G., Kerjaschki D., Gonda M., Nevins T., Rielle J. C., Brentjens J., Andres G. Expression and modulation of surface antigens in cultured rat glomerular visceral epithelial cells. J Histochem Cytochem. 1989 Nov;37(11):1675–1687. doi: 10.1177/37.11.2809176. [DOI] [PubMed] [Google Scholar]
  6. Couser W. G., Abrass C. K. Pathogenesis of membranous nephropathy. Annu Rev Med. 1988;39:517–530. doi: 10.1146/annurev.me.39.020188.002505. [DOI] [PubMed] [Google Scholar]
  7. D'Amore P. A. Modes of FGF release in vivo and in vitro. Cancer Metastasis Rev. 1990 Nov;9(3):227–238. doi: 10.1007/BF00046362. [DOI] [PubMed] [Google Scholar]
  8. Detwiler R. K., Falk R. J., Hogan S. L., Jennette J. C. Collapsing glomerulopathy: a clinically and pathologically distinct variant of focal segmental glomerulosclerosis. Kidney Int. 1994 May;45(5):1416–1424. doi: 10.1038/ki.1994.185. [DOI] [PubMed] [Google Scholar]
  9. Dijkstra C. D., Döpp E. A., Joling P., Kraal G. The heterogeneity of mononuclear phagocytes in lymphoid organs: distinct macrophage subpopulations in the rat recognized by monoclonal antibodies ED1, ED2 and ED3. Immunology. 1985 Mar;54(3):589–599. [PMC free article] [PubMed] [Google Scholar]
  10. Firth J. D. Effect of polycations on the function of the isolated perfused rat kidney. Clin Sci (Lond) 1990 Dec;79(6):591–598. doi: 10.1042/cs0790591. [DOI] [PubMed] [Google Scholar]
  11. Floege J., Alpers C. E., Burns M. W., Pritzl P., Gordon K., Couser W. G., Johnson R. J. Glomerular cells, extracellular matrix accumulation, and the development of glomerulosclerosis in the remnant kidney model. Lab Invest. 1992 Apr;66(4):485–497. [PubMed] [Google Scholar]
  12. Floege J., Alpers C. E., Sage E. H., Pritzl P., Gordon K., Johnson R. J., Couser W. G. Markers of complement-dependent and complement-independent glomerular visceral epithelial cell injury in vivo. Expression of antiadhesive proteins and cytoskeletal changes. Lab Invest. 1992 Oct;67(4):486–497. [PubMed] [Google Scholar]
  13. Floege J., Burns M. W., Alpers C. E., Yoshimura A., Pritzl P., Gordon K., Seifert R. A., Bowen-Pope D. F., Couser W. G., Johnson R. J. Glomerular cell proliferation and PDGF expression precede glomerulosclerosis in the remnant kidney model. Kidney Int. 1992 Feb;41(2):297–309. doi: 10.1038/ki.1992.42. [DOI] [PubMed] [Google Scholar]
  14. Floege J., Eng E., Lindner V., Alpers C. E., Young B. A., Reidy M. A., Johnson R. J. Rat glomerular mesangial cells synthesize basic fibroblast growth factor. Release, upregulated synthesis, and mitogenicity in mesangial proliferative glomerulonephritis. J Clin Invest. 1992 Dec;90(6):2362–2369. doi: 10.1172/JCI116126. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Floege J., Eng E., Young B. A., Johnson R. J. Factors involved in the regulation of mesangial cell proliferation in vitro and in vivo. Kidney Int Suppl. 1993 Jan;39:S47–S54. [PubMed] [Google Scholar]
  16. Floege J., Johnson R. J., Alpers C. E., Fatemi-Nainie S., Richardson C. A., Gordon K., Couser W. G. Visceral glomerular epithelial cells can proliferate in vivo and synthesize platelet-derived growth factor B-chain. Am J Pathol. 1993 Feb;142(2):637–650. [PMC free article] [PubMed] [Google Scholar]
  17. Floege J., Johnson R. J., Gordon K., Iida H., Pritzl P., Yoshimura A., Campbell C., Alpers C. E., Couser W. G. Increased synthesis of extracellular matrix in mesangial proliferative nephritis. Kidney Int. 1991 Sep;40(3):477–488. doi: 10.1038/ki.1991.235. [DOI] [PubMed] [Google Scholar]
  18. Floege J., Johnson R. J., Gordon K., Yoshimura A., Campbell C., Iruela-Arispe L., Alpers C. E., Couser W. G. Altered glomerular extracellular matrix synthesis in experimental membranous nephropathy. Kidney Int. 1992 Sep;42(3):573–585. doi: 10.1038/ki.1992.321. [DOI] [PubMed] [Google Scholar]
  19. Hughes S. E., Hall P. A. Immunolocalization of fibroblast growth factor receptor 1 and its ligands in human tissues. Lab Invest. 1993 Aug;69(2):173–182. [PubMed] [Google Scholar]
  20. Jeraj K., Vernier R. L., Sisson S. P., Michael A. F. A new glomerular antigen in passive Heymann's nephritis. Br J Exp Pathol. 1984 Aug;65(4):485–498. [PMC free article] [PubMed] [Google Scholar]
  21. Johnson R. J., Garcia R. L., Pritzl P., Alpers C. E. Platelets mediate glomerular cell proliferation in immune complex nephritis induced by anti-mesangial cell antibodies in the rat. Am J Pathol. 1990 Feb;136(2):369–374. [PMC free article] [PubMed] [Google Scholar]
  22. Johnson R. J., Iida H., Alpers C. E., Majesky M. W., Schwartz S. M., Pritzi P., Gordon K., Gown A. M. Expression of smooth muscle cell phenotype by rat mesangial cells in immune complex nephritis. Alpha-smooth muscle actin is a marker of mesangial cell proliferation. J Clin Invest. 1991 Mar;87(3):847–858. doi: 10.1172/JCI115089. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Johnson R. J., Pritzl P., Iida H., Alpers C. E. Platelet-complement interactions in mesangial proliferative nephritis in the rat. Am J Pathol. 1991 Feb;138(2):313–321. [PMC free article] [PubMed] [Google Scholar]
  24. Kanwar Y. S., Liu Z. Z., Kashihara N., Wallner E. I. Current status of the structural and functional basis of glomerular filtration and proteinuria. Semin Nephrol. 1991 Jul;11(4):390–413. [PubMed] [Google Scholar]
  25. Kerjaschki D., Farquhar M. G. Immunocytochemical localization of the Heymann nephritis antigen (GP330) in glomerular epithelial cells of normal Lewis rats. J Exp Med. 1983 Feb 1;157(2):667–686. doi: 10.1084/jem.157.2.667. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Kerjaschki D., Schulze M., Binder S., Kain R., Ojha P. P., Susani M., Horvat R., Baker P. J., Couser W. G. Transcellular transport and membrane insertion of the C5b-9 membrane attack complex of complement by glomerular epithelial cells in experimental membranous nephropathy. J Immunol. 1989 Jul 15;143(2):546–552. [PubMed] [Google Scholar]
  27. Kerjaschki D. The pathogenesis of membranous glomerulonephritis: from morphology to molecules. Virchows Arch B Cell Pathol Incl Mol Pathol. 1990;58(4):253–271. doi: 10.1007/BF02890080. [DOI] [PubMed] [Google Scholar]
  28. Klagsbrun M., Edelman E. R. Biological and biochemical properties of fibroblast growth factors. Implications for the pathogenesis of atherosclerosis. Arteriosclerosis. 1989 May-Jun;9(3):269–278. doi: 10.1161/01.atv.9.3.269. [DOI] [PubMed] [Google Scholar]
  29. Kriz W., Elger M., Nagata M., Kretzler M., Uiker S., Koeppen-Hageman I., Tenschert S., Lemley K. V. The role of podocytes in the development of glomerular sclerosis. Kidney Int Suppl. 1994 Feb;45:S64–S72. [PubMed] [Google Scholar]
  30. Lindner V., Majack R. A., Reidy M. A. Basic fibroblast growth factor stimulates endothelial regrowth and proliferation in denuded arteries. J Clin Invest. 1990 Jun;85(6):2004–2008. doi: 10.1172/JCI114665. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Mazué G., Bertolero F., Garofano L., Brughera M., Carminati P. Experience with the preclinical assessment of basic fibroblast growth factor (bFGF). Toxicol Lett. 1992 Dec;64-65 Spec No:329–338. doi: 10.1016/0378-4274(92)90205-x. [DOI] [PubMed] [Google Scholar]
  32. Rao T. K. Human immunodeficiency virus (HIV) associated nephropathy. Annu Rev Med. 1991;42:391–401. doi: 10.1146/annurev.me.42.020191.002135. [DOI] [PubMed] [Google Scholar]
  33. Rapraeger A. C., Krufka A., Olwin B. B. Requirement of heparan sulfate for bFGF-mediated fibroblast growth and myoblast differentiation. Science. 1991 Jun 21;252(5013):1705–1708. doi: 10.1126/science.1646484. [DOI] [PubMed] [Google Scholar]
  34. Ray P. E., Bruggeman L. A., Weeks B. S., Kopp J. B., Bryant J. L., Owens J. W., Notkins A. L., Klotman P. E. bFGF and its low affinity receptors in the pathogenesis of HIV-associated nephropathy in transgenic mice. Kidney Int. 1994 Sep;46(3):759–772. doi: 10.1038/ki.1994.331. [DOI] [PubMed] [Google Scholar]
  35. Reilly T. M., Taylor D. S., Herblin W. F., Thoolen M. J., Chiu A. T., Watson D. W., Timmermans P. B. Monoclonal antibodies directed against basic fibroblast growth factor which inhibit its biological activity in vitro and in vivo. Biochem Biophys Res Commun. 1989 Oct 31;164(2):736–743. doi: 10.1016/0006-291x(89)91521-0. [DOI] [PubMed] [Google Scholar]
  36. Salant D. J., Darby C., Couser W. G. Experimental membranous glomerulonephritis in rats. Quantitative studies of glomerular immune deposit formation in isolated glomeruli and whole animals. J Clin Invest. 1980 Jul;66(1):71–81. doi: 10.1172/JCI109837. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Schulze M., Baker P. J., Perkinson D. T., Johnson R. J., Ochi R. F., Stahl R. A., Couser W. G. Increased urinary excretion of C5b-9 distinguishes passive Heymann nephritis in the rat. Kidney Int. 1989 Jan;35(1):60–68. doi: 10.1038/ki.1989.8. [DOI] [PubMed] [Google Scholar]
  38. Sekiya S., Gotoh S., Yamashita T., Watanabe T., Saitoh S., Sendo F. Selective depletion of rat neutrophils by in vivo administration of a monoclonal antibody. J Leukoc Biol. 1989 Aug;46(2):96–102. doi: 10.1002/jlb.46.2.96. [DOI] [PubMed] [Google Scholar]
  39. Silver B. J., Jaffer F. E., Abboud H. E. Platelet-derived growth factor synthesis in mesangial cells: induction by multiple peptide mitogens. Proc Natl Acad Sci U S A. 1989 Feb;86(3):1056–1060. doi: 10.1073/pnas.86.3.1056. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Susani M., Schulze M., Exner M., Kerjaschki D. Antibodies to glycolipids activate complement and promote proteinuria in passive Heymann nephritis. Am J Pathol. 1994 Apr;144(4):807–819. [PMC free article] [PubMed] [Google Scholar]
  41. Takeuchi A., Yoshizawa N., Yamamoto M., Sawasaki Y., Oda T., Senoo A., Niwa H., Fuse Y. Basic fibroblast growth factor promotes proliferation of rat glomerular visceral epithelial cells in vitro. Am J Pathol. 1992 Jul;141(1):107–116. [PMC free article] [PubMed] [Google Scholar]
  42. Wallenstein S., Zucker C. L., Fleiss J. L. Some statistical methods useful in circulation research. Circ Res. 1980 Jul;47(1):1–9. doi: 10.1161/01.res.47.1.1. [DOI] [PubMed] [Google Scholar]
  43. Weise B., Janet T., Grothe C. Localization of bFGF and FGF-receptor in the developing nervous system of the embryonic and newborn rat. J Neurosci Res. 1993 Mar 1;34(4):442–453. doi: 10.1002/jnr.490340409. [DOI] [PubMed] [Google Scholar]
  44. Yaoita E., Kawasaki K., Yamamoto T., Kihara I. Variable expression of desmin in rat glomerular epithelial cells. Am J Pathol. 1990 Apr;136(4):899–908. [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES