Clinical Investigation

Kidney International (1994) 46, 1663–1673; doi:10.1038/ki.1994.466

Prevention of glomerulosclerosis by early cyclosporine treatment of experimental lupus nephritis

Eline C Bergijk1, Hans J Baelde1, Emile de Heer1 and Jan Anthonie Bruijn1

1Department of Pathology, University of Leiden, Leiden, The Netherlands

Correspondence: Eline C Bergijk, University of Leiden, Department of Pathology, AZL, Building 1, L1-Q, P.O. Box 9600, 2300 RC Leiden, The Netherlands.

Received 14 December 1993; Revised 8 July 1994; Accepted 11 July 1994.

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Abstract

Prevention of glomerulosclerosis by early cyclosporine treatment of experimental lupus nephritis. The influence of cyclosporine A (CsA) treatment on the development of glomerulonephritis and glomerulosclerosis was investigated in chronic graft-versus-host disease (GvHD), a murine model for lupus nephritis. The renal disease is characterized by the formation of IgG-containing electron-dense deposits along the glomerular basement membrane (GBM) and in the mesangium, followed by the onset of proteinuria which starts, varying per individual mouse, about six weeks after the induction of the disease. Glomerular mRNA levels for matrix molecules were increased from week 4, preceding mesangial matrix expansion and GBM thickening which occurred from week 6. These initial events finally led to development of glomerulosclerosis, and end-stage renal failure. Groups of mice received three intraperitoneal (i.p.) injections per week with different doses of CsA, and treatment was started 2, 4, or 6 weeks after induction of the disease. Treatment with 10 or 50 mg CsA/kg/week did not influence the development of glomerulonephritis or glomerulosclerosis. Injection of 100 mg CsA/kg/week delayed the onset of proteinuria only when treatment was started in week 2. In week 6 some mice had already developed proteinuria whereas others had not. Treatment with 250 mg CsA/kg/week starting in week 6 abrogated glomerulonephritis and glomerulosclerosis only in those animals which were not yet proteinuric at that time. This, despite comparable increased autoantibody levels against DNA, GBM, and renal tubular epithelium (RTE) in both treated and untreated GvHD mice. Further increase in proteinuria and development of glomerulosclerosis could not be prevented if the mice already had developed proteinuria when CsA treatment was started. Dot blot analysis and in situ hybridization showed significantly decreased mRNA levels for alpha1(I) and alpha1(IV) collagen in kidneys of CsA-treated mice as compared to those of untreated mice 12 weeks after induction of the disease, if the highest dose of CsA was administered before the onset of proteinuria. No effect on these whole-kidney mRNA levels was observed in mice which had already developed proteinuria before CsA injections were started. Increased mRNA expression for matrix molecules in this group and in untreated GvHD mice was observed mainly in the interstitium. The kidneys of the treated GvHD mice and those of mice injected with 250 mg CsA/kg/week without induction of GvHD showed no morphological signs of CsA nephrotoxicity. We conclude that treatment with 250 mg CsA/kg/week prevents the development of glomerulonephritis and glomerulosclerosis in this model of lupus nephritis, if started before the onset of proteinuria. This might result from a direct effect of CsA on matrix synthesis, since autoimmunity was not affected as reflected by unaltered autoantibody levels, which increased to a similar extent in both treated and untreated animals. Furthermore, our results may indicate the possible diagnostic and prognostic value of extracellular matrix steadystate mRNA levels in early stages of renal disease.

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References

  1. Bruijn JA, van Elven EH, Hogendoorn PCW, Corver WE, Hoedemaeker PJ, Fleuren GJ: Murine chronic graft-versus-host disease as a model for human lupus nephritis. Am J Pathol 130:639–641, 1988 | PubMed | ISI | ChemPort |
  2. Rolink AG, Gleichmann H, Gleichmann E: Diseases caused by reactions of T-lymphocytes to incompatible structures of the major histocompatibility complex. VII. Immune-complex glomerulonephritis. J Immunol 130:209–215, 1983 | PubMed | ISI | ChemPort |
  3. van Elven EH: Reactions of T-cells Cause SLE and Related Disorders, Academic Thesis, University of Amsterdam, Krips Repro Meppel, 1981
  4. Gleichmann E, Pals STP, Rolink AG, Radaszkiewicz T, Gleichmann H: Graft-versus-host reactions: Clues to the etiopathology of a spectrum of immunologycal diseases. Immunol Today 5:324–332, 1984 | Article | ISI |
  5. Via CS, Shearer GM: T-cell interactions in autoimmunity: Insights from a murine model of graft-versus-host disease. Immunol Today 9:207–213, 1988 | Article | PubMed | ISI | ChemPort |
  6. Pals ST, Radaszkiewicz T, Gleichmann E: Allosuppressor and allohelper T cells in acute and chronic graft-versus-host disease. IV. Activation of donor allosuppressor cells is confined to acute GvHD. J Immunol 132:1669–1675, 1984 | PubMed | ISI | ChemPort |
  7. Berguk EC, Munaut C, Baelde JJ, Prins F, Foidart JM, Hoedemaeker PJ, Bruijn JA: A histological study of the extracellular matrix during the development of glomerulosclerosis in murine chronic graft-versus-host disease. Am J Pathol 140:1147–1156, 1992
  8. Shevach EM: The effects of cyclosporin A on the immune system. Annu Rev Immunol 3:397–423, 1985 | Article | PubMed | ChemPort |
  9. Kay JE: Inhibitory effects of cyclosporin A on lymphocyte activation, in Cyclosporin. Mode of Action and Clinical Applications, edited by Thomson AW, Dordrecht/Boston/London, Kluwer Academic Publishers, 1989 pp 1–23
  10. Bolton C, Allsopp G, Cuzner ML: The effect of cyclosporin A on the adoptive transfer of experimental allergic encephalomyelitis in the Lewis rat. Clin Exp Immunol 47:127–132, 1982
  11. De Heer E, Daha MR, van Es LA: The autoimmune response in active Heymann's nephritis in Lewis rats is regulated by T-lymphocyte subsets. Cell Immunol 92:254–254, 1985
  12. Kaibara N, Hotokebuchi T, Takagishi K, Katsuki I: Paradoxical effects of cyclosporin A on collagen arthritis in rats. J Exp Med 158:2007–2015, 1983 | Article | PubMed | ChemPort |
  13. Gunn HC: Successful treatment of autoimmunity in (NZBxNZW)F1 mice with cyclosporin and (Nva2)-cyclosporin: I. Reduction of autoantibodies. Clin Exp Immunol 64:225–233, 1986
  14. Axelsen NH: Quantitative Immunoelectrophoresis, New developments and applications. Scand J Immunol (Suppl 2) 1975
  15. Bruijn JA, Hogendoorn PCW, Corver WE, van den Broek LJCM, Hoedemaeker PJ, Fleuren GJ: Pathogenesis of experimental lupus nephritis: A role for anti-basement membrane and anti-tubular brush border antibodies in murine chronic graft-versus-host disease. Clin Exp Immunol 79:115–122, 1990
  16. Baelde JJ, Berguk EC, Bruijn JA: Isolation and characterization of mouse glomerular basement membrane. J Clin Lab Immunol 33:17–20, 1990
  17. Chirgwin JM, Pryzbala AE, MacDonald RY, Rutter W: Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry 18:5294–5299, 1977
  18. Church GM, Gilbert W: Genomic sequencing. Proc Natl Acad Sci USA 81:1991, 1984 | Article | PubMed | ChemPort |
  19. Maniatis T, Fritsch EF, Sambrook J: Molecular Cloning, A Laboratory Manual. Cold Spring Harbor, Cold Spring Harbor Laboratory, 1982, pp 7.54–7.55
  20. Kurkinen M, Bernard MP, Barlow DP, Chow LT: Characterization of 64-, 123- and 182-base-pair exons in the mouse alpha2(IV)collagen gene. Nature 317:177–179, 1985 | Article | PubMed | ISI | ChemPort |
  21. Munaut C, Berguk EC, Baelde JJ, Noel A, Foidart JM, Bruijn JA: A molecular biological study of extracellular matrix components during the development of glomerulosclerosis in murine chronic graft-versus-host disease (GvHD). Lab Invest 67:580–587, 1992 | PubMed | ISI | ChemPort |
  22. Wilkinson DG, Green J: In situ hybridization and the threedimensional reconstruction of serial sections, in Postimplantation Mammalian Embryos. A Practical Approach, edited by Copp AJ, Coekhoft DL, New York IRL Press, 1990, pp 155–171
  23. Laurie GW, Horikoshi S, Killen PD, Segui-Real B, Yamada Y: In situ hybridization reveals temporal and spatial changes in cellular expression of mRNA for a laminin receptor, laminin, and basement membrane (type IV) collagen in the developing kidney. J Cell Biol 109:1351–1362, 1989
  24. Borel JF: Mechanism of action of cyclosporin A and rationale for use in nephrotic syndrome. Clin Nephrol 35:S23–S30, 1991
  25. Bartlett RR, Popovic S, Raiss RX: Development of autoimmunity in MRL/lpr mice and the effects of drugs on this murine disease. Scand J Rheumatol 75:290–299, 1988
  26. Ren K, van Liew JB, Nobel B: The effect of cyclosporin A on disease progression in proliferative immune complex glomerulonephritis. Clin Immunol Immunopathol 66:107–113, 1993
  27. Siekierka JJ, Sigal NH: FK-506 and cyclosporin A: Immunosuppressive mechanism of action and beyond. Curr Opin Immunol 4:548–552, 1992 | Article | PubMed | ChemPort |
  28. Hess AD: Mechanisms of action of cyclosporine: Considerations for the treatment of autoimmune diseases. Clin Immunol Immunopathol 68:220–228, 1993
  29. Erlanger BF: Do we know the site of action of cyclosporin. Immunol Today 13:487–490, 1992
  30. Herold KC, Lancki DW, Moldwin RL, Fitch FW: Immunosuppressive effects of cyclosporin A on cloned T cells. J Immunol 136:1315–1321, 1986
  31. Bickel M, Tsuda H, Amstad P, Evequoz V, Mergenhagen SE, Wahl SM, Pluznik DH: Differential regulation of colony-stimulating factors and interleukin 2 production by cyclosporin A. Proc Natl Acad Sci USA 84:3274–3277, 1987 | Article | PubMed | ChemPort |
  32. Shaw J, Meerovitch K, Elliott JF, Bleackley RC, Paetkau V: Induction, suppression and superinduction of lymphokine mRNA in T lymphocytes. Mol Immunol 24:409–419, 1987 | Article | PubMed | ChemPort |
  33. Marone G, de Paulis A, Casolaro V, Ciccarelli A, Spadaro G, Cirillo R: In vitro and in vivo characterization of the anti-inflammatory effects of cyclosporin A. Int Arch Allergy Immunol 99:279–283, 1992
  34. Wenzel-Seifert K, Grünbaum L, Seifert R: Differential inhibition of human neutrophil activation by cyclosporins A, D, and H. Cyclosporin H is a potent and effective inhibitor of formyl peptide-induced superoxide formation. J Immunol 147:1940–1946, 1991
  35. Bunjes D, Hardt C, Rollinghoff M, Wagner H: Cyclosporin A mediates immunosuppression of primary cytotoxic T cell responses by impairing the release of interleukin 1 and interleukin 2. Eur J Immunol 11:657–661, 1981 | PubMed | ChemPort |
  36. Granelli-Piperno A, Inaba K, Steinman R: Stimulation of lymphokine release from T lymphoblasts. Requirement for mRNA synthesis and inhibition by cyclosporin A. J Exp Med 160:1792–1802, 1984 | Article | PubMed | ChemPort |
  37. Manca F, Kunkl A, Celada F: Inhibition of the accessory function of murine macrophages in vitro by cyclosporin. Transplantation 39:644–649, 1985 | PubMed | ChemPort |
  38. Auch-Schwelk W, Bossaller C, Gotze S, Thelen J, Fleck E: Endothelial and vascular smooth muscle function after chronic treatment with cyclosporin A. J Cardiovasc Pharmacol 21:435–440, 1993 | PubMed | ChemPort |
  39. Leszczynski D, Zhao Y, Yeagley TJ, Foegh ML: Direct and endothelial cell-mediated effect of cyclosporin A on the proliferation of rat smooth muscle cells. Am J Pathol 142:149–155, 1993
  40. Zoja C, Furci L, Ghilardi F, Zilio P, Benigni A, Remuzzi G: Cyclosporin-induced endothelial cell injury. Lab Invest 55:455, 1986 | PubMed | ISI | ChemPort |
  41. Benigni A, Morigi M, Perico N, Zoja C, Amuchastegui CS, Piccinelli A, Donadelli R, Remuzzi G: The acute effect of FK506 and cyclosporine on endothelial cell function and renal vascular resistance. Transplantation 54:775–780, 1992 | PubMed | ChemPort |
  42. Hedges S, Agace W, Svensson M, Svanborg C: Cyclosporin A does not inhibit IL-1alpha-induced epithelial cell IL-6 secretion. Scand J Immunol 37:581–586, 1993
  43. Fukatsu A, Matsuo S, Tamai H, Sakamoto N, Matsuda T, Hirano T: Distribution of interleukin-6 in normal and diseased human kidney. Lab Invest 65:61–65, 1991 | PubMed | ISI | ChemPort |
  44. Horii Y, Iwano M, Hirata E, Shiiki H, Fujii Y, Dohi K, Ishikawa H: Role of interleukin-6 in the progression of mesangial proliferative glomerulonephritis. Kidney Int 43(Suppl 39):S71–S75, 1993
  45. Radeke HH, Kuster S, Kaever V, Resch K: Effects of cyclosporin and FK-506 on glomerular mesangial cells. Evidence for direct inhibition of thromboxane synthase by low cyclosporin concentrations. Eur J Clin Pharmacol 44(Suppl 1):S11–S16, 1993 | Article | PubMed | ISI | ChemPort |
  46. Bruggeman LA, Pellicoro JA, Horigan EA, Klotman PE: Thromboxane and prostacyclin differentially regulate murine extracellular matrix gene expression. Kidney Int 43:1219–1225, 1993 | PubMed | ISI | ChemPort |
  47. Collins DM, Coffman TM, Klotman PE: The role of thromboxane in the pathogenesis of acute renal failure, in Acute Renal Failure, edited by Solez K, Racusen LC, New York, Marcel Dekker, Inc., 1991, pp 13–47
  48. Berguk EC, Baelde HJ, de Heer E, Killen PD, Bruijn JA: Specific accumulation of fibronectin in experimental glomerulosclerosis. (manuscript submitted for publication)
  49. Bruijn JA, Berguk EC, de Heer E, Fleuren GJ, Hoedemaeker PJ: Induction and progression of experimental lupus nephritis: Exploration of a pathogenetic pathway. (editorial review) Kidney Int 41:5–13, 1992
  50. Wiggins R, Goyal M, Merritt S, Killen PD: Vascular adventitial cell expression of collagen I messenger ribonucleic acid in anti-glomerular basement membrane antibody-induced crescentic nephritis in the rabbit. Lab Invest 68:557–565, 1993 | PubMed | ISI | ChemPort |
  51. Striker LJ: Modern renal biopsy interpretation: Can we predict glomerulosclerosis? Semin Nephrol 13:508–515, 1993 | PubMed | ISI | ChemPort |
  52. Mihatsch MJ, Thiel G, Ryffel B: Renal side-effects of cyclosporin A with special reference to autoimmune diseases. Br J Dermatol 122(Suppl 36):101–115, 1990
  53. Nast CC, Adler SG, Artishevsky A, Kresser CT, Ahmed K, Anderson PS: Cyclosporin induces elevated procollagen alpha1(I) mRNA levels in the rat renal cortex. Kidney Int 39:631–638, 1991 | PubMed |
  54. Wolf G, Neilson EG: Increases in levels of collagen types I and IV messenger ribonucleic acid in murine kidneys after treatment with cyclosporin. Nephron 60:87–91, 1992
  55. Wood A, Adu D, Birtwistle RJ, Brewer DB, Michael J: Cyclosporin A and anti-glomerular basement membrane antibody glomerulonephritis in rats. Br J Exp Pathol 69:189–195, 1988

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