Advertisement

The clinical investigator

, Volume 70, Issue 9, pp 857–864 | Cite as

Mesangial cells in the pathogenesis of progressive glomerular disease in animal models

  • J. Floege
  • R. J. Johnson
  • W. G. Couser
Guest Lecture, “Gesellschaft für Nephrologie”, 23rd Congress

Summary

Increasing evidence supports a role for glomerular mesangial cell proliferation and overproduction of extracellular matrix by mesangial cells in the development of focal or diffuse glomerulosclerosis. Experimental data obtained mainly in the chronic progressive remnant kidney model and in the acute mesangioproliferative anti-Thy 1.1 glomerulonephritis in rats have shed some insights into the factors governing mesangial cell proliferation and matrix synthesis in vivo. In these experimental models, mesangial cell activation can be demonstrated early in the course of disease as exemplified by the de novo expression by the mesangial cell of a smooth muscle “specific” actin isotype (i.e., α-smooth muscle actin). Following mesangial cell activation, cellular proliferation ensues both in the acute anti-Thy 1.1 model and, to a lesser degree, in the chronic remnant kidney model. While a multitude of mitogens for mesangial cells has been proposed on the basis of in vitro experiments, the factors involved in the regulation of mesangial cell proliferation in vivo remain largely undefined. Three growth factors which may have important roles in the in vivo mesangioproliferative response are platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), and transforming growth factor-β (TGF-β). All three cytokine growth factors are present in various inflammatory cells as well as in mesangial cells themselves, thereby allowing these factors to mediate cell proliferation by either paracrine and/or autocrine pathways. In vivo studies show that PDGF, bFGF, and TGF-β participate in the mesangial cell proliferation and/or the mesangial matrix expansion that follows mesangial cell injury with anti-Thy 1.1 antibody. Preliminary evidence also suggests the participation of some of these factors in the mesangial cell proliferation and matrix accumulation that is present in chronic glomerular disease such as in the remnant kidney model. In addition, experiments with transgenic mice suggest the importance of other growth factors, such as growth hormone, in the development of glomerular cell proliferation, matrix expansion, and glomerulosclerosis. Further elucidation of such polypeptide growth factors involved in glomerular pathology may ultimately result in the design of new therapeutic strategies to prevent or treat the progression of renal diseases.

Key words

Mesangial cells Matrix Glomerulosclerosis Proliferation Cytokines 

Abbreviations

bFGF

basic fibroblast growth factor

PDGF

platelet-derived growth factor

TGF-β

transforming growth factor β

GFR

glomerular filtration rate

Ig

Immunoglobulin

PCNA

proliferating cell nuclear antigen

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Alpers CE, Hudkins KL, Grown AM, Johnson RJ (1992) Enhanced expression of “muscle-specific” actin in glomerulonephritis. Kidney Int 41:1134–1142.CrossRefGoogle Scholar
  2. 2.
    Bagchus WM, Hoedemaeker PJ, Rozing J, Bakker WW (1986) Glomerulonephritis induced by monoclonal anti-Thy 1.1 antibodies. Lab Invest 55:680–687.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Bohle A, Mackensen-Haen S, Gise H von (1986) Importance of tubulointerstitial changes in glomerular excretory and urine concentrating function of the kidney. Zentralbl Allg Pathol 132:351–363.PubMedGoogle Scholar
  4. 4.
    Border WA (1988) Distinguishing minimal-change disease from mesangial disorders. Kidney Int 34:419–430.CrossRefGoogle Scholar
  5. 5.
    Border WA, Okuda S, Languino LR, Sporn MB, Ruoslahti E (1990) Suppression of experimental glomerulonephritis by antiserum against transforming growth factor β1 (letter). Nature 346:371–374.CrossRefGoogle Scholar
  6. 6.
    Border WA, Okuda S, Languino LR, Ruoslahti E (1990) Transforming growth factor-β regulates production of proteoglycans by mesangial cells. Kidney Int 37:689–695.CrossRefGoogle Scholar
  7. 7.
    Brazy PC, Kopp JB, Klotman PE (1991) Glomerulosclerosis and progressive renal disease. In: Keane WF, Stein JH (eds) Contemporary issues of nephrology 24. Churchill Livingstone, New York, pp 11–35.Google Scholar
  8. 8.
    Coimbra T, Wiggins R, Noh JW, Merritt S, Phan SH (1991) Transforming growth factor-β production in anti-glomerular basement membrane disease in the rabbit. Am J Pathol 138:223–234.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Drenckhahn D, Schnittler H, Nobiling R, Kriz W (1990) Ultrastructural organization of contractile proteins in rat glomerular mesangial cells. Am J Pathol 137:1343–1351.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Doi T, Striker LJ, Kimata K, Peten EP, Yamada Y, Striker GE (1991) Glomerulosclerosis in mice transgenic for growth hormone. Increased mesangial extracellular matrix is correlated with kidney mRNA levels. J Exp Med 173:1287–1290.CrossRefGoogle Scholar
  11. 11.
    Floege J, Johnson RJ, Gordon K, Iida H, Pritzl P, Yoshimura A, Campbell C, Alpers CE, Couser WG (1991) Increased synthesis of extracellular matrix in mesangial proliferative nephritis. Kidney Int 40:477–488.CrossRefGoogle Scholar
  12. 12.
    Floege J, Topley N, Hoppe J, Barrett TB, Resch K (1991) Mitogenic effect of platelet-derived growth factor in human glomerular mesangial cells: modulation and/or suppression by inflammatory cytokines. Clin Exp Immunol 86:334–341.CrossRefGoogle Scholar
  13. 13.
    Floege J, Burns MW, Alpers CE, Yoshimura A, Pritzl P, Gordon K, Seifert RA, Bowen-Pope DF, Couser WG, Johnson RJ (1992) Glomerular cell proliferation and PDGF expression precedes glomerulosclerosis in the remnant kidney model. Kidney Int 41:297–309.CrossRefGoogle Scholar
  14. 14.
    Floege J, Eng E, Young B, Johnson RJ (1992) Factors involved in the regulation of mesangial cell proliferation in vitro and in vivo. Kidney Int (in press).Google Scholar
  15. 15.
    Floege J, Alpers CE, Burns MW, Pritzl P, Gordon K, Couser WG, Johnson RJ (1992) Glomerular cells, extracellular matrix accumulation, and the development of glomerulosclerosis in the remnant kidney model. Lab Invest 66:485–497.PubMedGoogle Scholar
  16. 16.
    Fogo A, Ichikawa I (1989) Evidence for the central role of glomerular growth promoters in the development of sclerosis. Semin Nephrol 9:329–342.PubMedGoogle Scholar
  17. 17.
    Fogo A, Yoshida Y, Glick AD, Homma T, Ichikawa I (1988) Serial micropuncture analysis of glomerular function in two rat models of glomerular sclerosis. J Clin Invest 82:322–330.CrossRefGoogle Scholar
  18. 18.
    Goldman M, Baran D, Druet P (1988) Polyclonal activation and experimental nephropathies. Kidney Int 34:141–150.CrossRefGoogle Scholar
  19. 19.
    Haralson MA, Jacobson HR, Hoover RL (1987) Collagen polymorphism in cultured rat kidney mesangial cells. Lab Invest 57:513–523.PubMedGoogle Scholar
  20. 20.
    Horii Y, Muraguchi A, Iwano M, Matsuda T, Hirayama T, Yamada H, Fujii Y, Dohi K, Ichikawa H, Ohmoto Y, Yoshizaki K, Hirano T, Kishimoto T (1989) Involvement of interleukin-6 in mesangial proliferative glomerulonephritis. J Immunol 143:3949–3955.Google Scholar
  21. 21.
    Ichikawa I, Yoshida Y, Fogo A, Purkerson ML, Klahr S (1988) Effect of heparin on the glomerular structure and function of remnant nephrons. Kidney Int 34:638–644.CrossRefGoogle Scholar
  22. 22.
    Iida H, Seifert R, Alpers CE, Gronwald RGK, Philips PE, Pritzl P, Gordon K, Gown AM, Ross R, Bowen-Pope DF, Johnson RJ (1991) Platelet-derived growth factor (PDGF) and PDGF receptor are induced in mesangial proliferative nephritis in the rat. Proc Natl Acad Sci USA 88:6560–6564.CrossRefGoogle Scholar
  23. 23.
    Ishimura E, Sterzel RB,Budde K, Kashgarian M (1989) Formation of extracellular matrix by cultured rat mesangial cells. Am J Pathol 134:843–855.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Jaffer F, Daunders C, Shultz P, Throckmorton D, Weinshell E, Abboud HE (1989) Regulation of mesangial cell growth by polypeptide mitogens. Inhibitory role of transforming growth factor β. Am J Pathol 135:261–269.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Johnson RJ, Garcia RL, Pritzl P, Alpers CE (1990) Platelets mediate glomerular cell proliferation in immune complex nephritis induced by anti-mesangial cell antibodies in the rat. Am J Pathol 136:369–374.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Johnson RJ, Iida H, Alpers CE, Majesky MW, Schwartz SM, Pritzl P, Gordon K, Gown AM (1991) Expression of smooth muscle cell phenotype by rat mesangial cells in immune complex nephritis. J Clin Invest 87:847–858.CrossRefGoogle Scholar
  27. 27.
    Johnson RJ, Alpers CE, Yoshimura A, Lombardi D, Pritzl P, Floege J, Schwartz SM (1992) Renal injury from angiotensin-II mediated hypertension. Hypertension (in press).Google Scholar
  28. 28.
    Johnson RJ, Raines E, Floege J, Yoshimura A, Pritzl P, Alpers C, Ross R (1992) Inhibition of mesangial cell proliferation and matrix expansion in glomeruloneprhitis in the rat by antibody to platelet derived growth factor. J Exp Med (in press).Google Scholar
  29. 29.
    Johnson RJ, Floege J, Yoshimura A, Iida H, Couser WG, Alpers CE (1992) The activated mesangial cell: a glomerular “myofibroblast”? J Am Soc Nephrol (in press).Google Scholar
  30. 30.
    Lovett DH, Johnson RJ, Marti HP, Martin J, Davies M, Couser WG (1992) Structural characterization of the mesangial cell type IV collagenase and enhanced expression in a model of immune complex-mediated glomerulonephritis. Am J Pathol (in press).Google Scholar
  31. 31.
    Morita T, Churg J (1983) Mesangiolysis. Kidney Int 24:1–9.CrossRefGoogle Scholar
  32. 32.
    Novick AC, Gephardt G, Guz B, Steinmuller D, Tubbs RR (1991) Long-term follow-up after partial removal of a solitary kidney. N Engl J Med 325:1058–1062.CrossRefGoogle Scholar
  33. 33.
    O'Donoghue DJ, Darvill A, Ballardie FW (1991) Mesangial cell autoantigens in immunoglobulin-A nephropathy and Henoch-Schönlein purpura. J Clin Invest 88:1522–1530.CrossRefGoogle Scholar
  34. 34.
    Okuda S, Languino LR, Ruoslahti E, Border WA (1990) Elevated expression of transforming growth factor-β and proteoglycan production in experimental glomerulonephritis. J Clin Invest 86:453–462.CrossRefGoogle Scholar
  35. 35.
    Oomura A, Nakamura T, Arakawa M, Ooshima A, Isemura M (1989) Alterations in the extracellular matrix components in human glomerular diseases. Virchows Archiv [A] 415:151–159.CrossRefGoogle Scholar
  36. 36.
    Pabst R, Sterzel RB (1983) Cell renewal of glomerular cell types in normal rats. An autoradiographic study. Kidney Int 24:626–631.CrossRefGoogle Scholar
  37. 37.
    Pesce CM, Striker LJ, Peten E, Elliot S, Striker GE (1991) Glomerulosclerosis at both early and late stages is associated with increased cell turnover in mice transgenic for growth hormone. Lab Invest 65:601–605.PubMedGoogle Scholar
  38. 38.
    Purkerson ML, Tollefsen DM, Klahr S (1988) N-desulfated/acetylated heparin ameliorates the progression of renal disease in rats with subtotal renal ablation. J Clin Invest 81:69–74.CrossRefGoogle Scholar
  39. 39.
    Radeke HH, Resch K (1992) The inflammatory function of renal glomerular mesangial cells and their interaction with the cellular immune system. Clin Investig 70:825–842.CrossRefGoogle Scholar
  40. 40.
    Rennke HG (1986) Structural alterations associated with glomerular hyperfiltration. In: Mitch WE, Brenner BM, Stein JH (eds) The progressive nature of renal disease. Churchill Livingstone, New York, pp 111–131.Google Scholar
  41. 41.
    Ross R (1989) The pathogenesis of atherosclerosis: an update. N Engl J Med 314:488–500.CrossRefGoogle Scholar
  42. 42.
    Schlöndorff D (1987) The glomerular mesangial cell: an expanding role for a specialized pericyte. FASEB J 1:272–281.CrossRefGoogle Scholar
  43. 43.
    Segal R, Fine LG (1989) Polypeptide growth factors and the kidney. Kidney Int 36 [Suppl 27]:S2-S10.Google Scholar
  44. 44.
    Shea SM, Raskova J, Morrison AB (1978) A stereologic study of glomerular hypertrophy in the subtotally nephrectomized rat. Am J Pathol 90:201–210.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Stahl RAK, Low I, Schoeppe W (1988) Progressive renal failure in a patient after one and two-thirds nephrectomy. Klin Wochenschr 66:508–510.CrossRefGoogle Scholar
  46. 46.
    Stahl RAK, Thaiss F, Schoeppe W, Wenzel U, Helmchen U (1990) Development of progressive glomerular disease in the rat by repetitive injection of an antibody directed to mesangial cells (abstract). J Am See Nephrol 4:642.Google Scholar
  47. 47.
    Sterzel RB, Lovett DH (1988) Interactions of inflammatory and glomerular cells in the response to glomerular injury. In: Brenner BM, Stein JH, Wilson CB (eds) Contemporary issues of nephrology 18. Churchill Livingstone, New York, pp 137–173.Google Scholar
  48. 48.
    Sterzel RB, Pabst R (1982) The temporal relationship between glomerular cell proliferation and monocyte infiltration in experimental glomerulonephritis. Virchows Arch 38:337–350.CrossRefGoogle Scholar
  49. 49.
    Striker LJ, Peten EP, Elliot SJ, Doi T, Striker GE (1991) Mesangial cell turnover: effect of heparin and peptide growth factors. Lab Invest 64:446–456.Google Scholar
  50. 50.
    Van Goor H, Fidler V, Weening J, Grond J (1992) Determinants of focal and segmental glomerulosclerosis in the rat after renal ablation. Lab Invest (in press).Google Scholar
  51. 51.
    Yamamoto T, Wilson CB (1987) Quantitative and qualitative studies of antibody-induced mesangial cell damage in the rat. Kidney Int 32:514–525.CrossRefGoogle Scholar
  52. 52.
    Yoshioka K, Tohda M, Takemura T, Akano N, Matsubara K, Ooshima A, Maki S (1990) Distribution of type I collagen in human kidney diseases in comparison with type III collagen. J Pathol 162:141–148.CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • J. Floege
    • 1
  • R. J. Johnson
    • 2
  • W. G. Couser
    • 2
  1. 1.Abteilung Nephrologie OE 6840Medizinische Hochschule HannoverHannover 61Germany
  2. 2.Division of NephrologyUniversity of WashingtonSeattle

Personalised recommendations