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Clinical and Experimental Nephrology

, Volume 2, Issue 4, pp 307–312 | Cite as

Mechanisms of progressive glomerulosclerosis and tubulointerstitial fibrosis

  • Richard J. Johnson
  • Christian Hugo
  • Leah Haseley
  • Raimund Pichler
  • James Bassuk
  • Susan Thomas
  • Shinichi Suga
  • William G. Couser
  • Stuart J. Shankland
Frontiers of Nephrology Part 3: Glomerular Scarring and Interstitial Fibrosis

Abstract

In this paper we provide an overview of the cellular changes that accompany progressive glomerulosclerosis and tubulointerstitial fibrosis. Emphasis is placed on the role of platelet-derived growth factor (PDGF) in the proliferation of the mesangial cell and interstitial fibroblast. PDGF also stimulates the synthesis and expression of a protein called secreted protein acidic and rich in cysteine (SPARC) and of thrombospondin 1 (TSP1). TSP1 may have an important role in the conversion of transforming growth factor (TGF)-β from its latent to active form. In turn, TGF-β appears to have a major role in mediating the extracellular matrix deposition that occurs with progressive glomerular and interstitial scarring.

Key words

glomerulosclerosis interstitial fibrosis PDGF TGF-β SPARC thrombospondin 1 

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References

  1. 1.
    Mitch WE, Walser M, Buffington GA, Lemann J Jr. A simple method of estimating progression of chronic renal failure. Lancet 1976; 2: 1326–1328.CrossRefPubMedGoogle Scholar
  2. 2.
    Brenner BM, Meyer TW, Hostetter TH. Dietary protein intake and the progressive nature of kidney disease: the role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis in aging, renal ablation, and intrinsic renal disaase. N Engl J Med 1982: 307: 652–659.CrossRefPubMedGoogle Scholar
  3. 3.
    Bidani AK, Griffin KA. Experimental models of renal mass reduction and their relevance to clinical medicine. Kidney: A Current Survey of World Literature 1995; 4: 4–9.Google Scholar
  4. 4.
    Brenner BM, Lawler EV, Mackenzie HS. The hyperfiltration theory: a paradigm shift in nephrology. Kidney Int 1996; 49 1774–1777.CrossRefPubMedGoogle Scholar
  5. 5.
    Anderson S, Meyer TW, Rennke HG, Brenner BM. Control of glomerular hypertension limits glomerular injury in rats with reduced renal mass. J Clin Invest 1985; 76: 612–619.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Zatz R, Dunn BR, Meyer TW, Anderson S, Rennke HG, Brenner BM. Prevention of diabetic glomerulopathy by pharmacological amelioration of glomerular capillary hypertension. J Clin Invest 1986; 77: 1925–1930.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Hostetter TH, Meyer, TW, Rennke HG, Brenner BM, Noddin JA, Sandstrom DS. Chronic effects of dietary protein in the rat with intact and reduced renal mass. Kidney Int 1986; 30: 509–517.CrossRefPubMedGoogle Scholar
  8. 8.
    Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med 1993; 329: 1456–1462.CrossRefPubMedGoogle Scholar
  9. 9.
    Ruggenenti P, Perna A, Mosconi L, Matalone M, Garini G, Salvadori M, Zoccali C, Scolari F, Maggiore Q, Tognoni G, Remuzzi G. Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, nondiabetic nephropathy. Lancet 1997; 349: 1857–1863.CrossRefGoogle Scholar
  10. 10.
    Klahr S, Levey AS, Beck GJ, Caggiula AW, Hunsicker L, Kusek JW, Striker G. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of diet in renal disease study group. N Engl J Med 1994; 330: 877–884.CrossRefPubMedGoogle Scholar
  11. 11.
    Pedrini MT, Levey AS, Lau J, Chalmers TC, Wang PH. The effect of dietary protein restriction on the progresion of diabetic and nondiabetic renal diseases: a metaanalysis. Ann Intern Med 1996; 124: 627–632.CrossRefPubMedGoogle Scholar
  12. 12.
    Morigi M, Zoja C, Figliuzzi M, Foppolo M, Micheletti G, Bontempelli M, Saronni M, Remuzzi G, Remuzzi A. Fluid shear stress modulates surface expression of adhesion molecules by endothelial cells. Blood 1995; 85: 1696–1703.PubMedGoogle Scholar
  13. 13.
    Riser BL, Cortes P, Zhao X, Bernstein J, Dumler F, Narins RG, Hassett CC, Sastry KSS, Atherton J, Holcomb MA. Intraglomerular pressure and mesangial stretching stimulate extracellular matrix formation in the rat. J Clin Invest 1992; 90: 1932–1943.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Bruzzi I, Benigni A, Remuzzi G. Role of increased glomerular protein traffic in the progression of renal failure. Kidney Int 1997; 62 (suppl): S29-S31.Google Scholar
  15. 15.
    Remuzzi G, Bertani T. Is glomerulosclerosis a consequence of altered glomerular permeability to macromolecules? Kidney Int 1990; 38: 384–394.CrossRefPubMedGoogle Scholar
  16. 16.
    Gröne EF, Walli AK, Gröne HJ, Miller B, Seidel D. The role of lipids in nephrosclerosis and glomerulosclerosis Atherosclerosis 1994; 107: 1–13.CrossRefPubMedGoogle Scholar
  17. 17.
    Fogo A, Ichikawa I. Evidence for the central role of glomerular growth promoters in the development of sclerosis. Semin Nephrol 1989; 9: 329–342.PubMedGoogle Scholar
  18. 18.
    He C, Esposito C, Phillips C, Zalups RK, Henderson DA, Striker GE, Striker JL. Dissociation of glomerular hypertrophy, cell proliferation, and glomerulosclerosis in mouse strains heterozygous for a mutation (Os) which induces a 50% reduction in nephron number. J Clin Invest 1996; 97: 1242–1249.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Johnson RJ. The glomerular response to injury: progression or resolution? Kidney Int 1994; 45: 1769–1782.CrossRefPubMedGoogle Scholar
  20. 20.
    Johnson RJ, Garcia R, Pritzl P, Alpers CE. Platelets mediate glomerular cell proliferation in immune complex nephritis in the rat induced by anti-mesangial cell antibodies. Am J Pathol 1990; 136: 369–374.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Johnson RJ, Raines E, Floege J, Yoshimura A, Pritzl P, Alpers CE, Ross R Inhibition of mesangial cell proliferation and matrix expression in glomerulonephritis by antibody to platelet derived growth factor. J Exp Med 1992; 175: 1413–1416.CrossRefPubMedGoogle Scholar
  22. 22.
    Paizis K, Polihronis M, Kirkland G, Osvath S, Power DA. Expression of HB-EGF mRNA in models of mesangial (MC) and glomerular epithelial cell (GEC) injury. J Am Soc Nephrol 1995; 6: 847 (abstr).Google Scholar
  23. 23.
    Fukuda K, Yanagida T, Okuda S, Tamaki K, Ando T, Fujishima M. Role of endothelin as a mitogen in experimental glomerulonephritis in rats. Kidney Int 1996; 49: 1320–1329.CrossRefPubMedGoogle Scholar
  24. 24.
    Johnson RJ, Iida H, Alpers CE, Majesky MW, Schwartz SM, Pritzl P, Gordon K, Gown AM. Expression of smooth muscle cell phenotype by rat mesangial cell in immune complex nephritis. J Clin Invest 1991; 87: 847–858.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Inui K, Yoshimura A, Uda S, Iwasaki S, Ideura T, Takahashi K. Glomerular expression of a binding protein specific for smooth muscle actin (calponin) in experimental and human proliferative glomerulonephritis. J Am Soc Nephrol 1995; 6: 422 (abstr).Google Scholar
  26. 26.
    Floege J, Johnson RJ, Gordon K, Iida H, Pritzl P, Yoshimura A, Campbell C, Alpers CE, Couser WG. Increased synthesis of extracellular matrix in mesangial proliferative nephritis. Kidney Int 1991; 40: 477–488.CrossRefPubMedGoogle Scholar
  27. 27.
    Pichler RH, Bassuk JA, Hugo C, Reed MJ, Eng E, Gordon KL, Pippin J, Alpers CE, Couser WG, Sage EH, Johnson RJ. SPARC is expressed by mesangial cells in experimental mesangial proliferative nephritis and inhibits platelet-derived-growth-factor-mediated mesangial cell proliferation in vitro. Am J Pathol 1996; 148: 1153–1167.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Border WA, Okuda S, Languino LR, Sporn MB, Ruoslahti E. Suppression of experimental glomerulonephritis by antiserum against transforming growth factor β1. Nature 1990; 346: 371–374.CrossRefPubMedGoogle Scholar
  29. 29.
    Tomooka S, Border WA, Marshall BC, Noble NA. Glomerular matrix accumulation is linked to the inhibition of the plasmin protease system. Kidney Int 1992; 42: 1462–1469.CrossRefPubMedGoogle Scholar
  30. 30.
    Marinides GN, Suchard SJ, Mookerjee BK. Role of thrombospondin in mesangial cell growth: possible existence of an autocrine feedback growth circuit. Kidney Int 1994; 46: 350–357.CrossRefPubMedGoogle Scholar
  31. 31.
    Taraboletti G, Morigi M, Figliuzzi M, Giavazzi R, Zoja C, Remuzzi G. Thrombospondin induces glomerular mesangial cell adhesion and migration. Lab Invest 1992; 67: 566–571.PubMedGoogle Scholar
  32. 32.
    Schultz-Cherry S, Ribeiro S, Gentry L, Murphy-Ullrich JE. Thrombospondin binds and activates the small and large forms of latent transforming growth factor-beta in a chemically defined system. J Biol Chem 1994; 269: 26775–26782.PubMedGoogle Scholar
  33. 33.
    Hugo C, Pichler R, Meek R, Gordon K, Kyriakides T, Floege J, Bornstein P, Couser WG, Johnson RJ. Thrombospondin 1 is expresed by proliferating mesangial cells and is up-regulated by PDGF and bFGF in vivo. Kidney Int 1995; 48: 1846–1856.CrossRefPubMedGoogle Scholar
  34. 34.
    Eng E, Floege J, Young BA, Couser WG, Johnson RJ. Does extracellular matrix expansion in glomerular disease require mesangial cell proliferation? Kidney Inr 1994; 45: S45-S48.Google Scholar
  35. 35.
    Floege J, Burns MW, Alpers CE, Yoshimura A, Pritzl P, Gordon K, Seifert RA, Bowen-Pope DF, Couser WG, Johnson RJ. Glomerular cell proliferation and PDGF expression precede glomerulosclerosis in the remnant kidney model. Kidney Int 1992; 41: 297–309.CrossRefPubMedGoogle Scholar
  36. 36.
    Wu LL, Cox A, Roe CJ, Dziadek, M, Cooper ME, Gilbert RE. Transforming growth factor β1 and renal injury following subtotal nephrectomy in the rat:role of the reninangiotensin system. Kidney Int 1997; 51: 1553–1567.CrossRefPubMedGoogle Scholar
  37. 37.
    Junaid A, Hostetter TH, Rosenberg ME. Interaction of angiotensin II and TGF-β in the rat remnant kidney. J Am Soc Nephrol 1997; 8: 1732–1738.PubMedGoogle Scholar
  38. 38.
    Sugiyama H, Kashihara N, Makino H, Yamasaki Y, Ota Z. Apoptosis in glomerular sclerosis. Kidney Int 1996; 49: 103–111.CrossRefPubMedGoogle Scholar
  39. 39.
    Baker AJ, Mooney A, Hughes J, Lombardi D, Floege J, Johnson RJ, Savill J. Mesangial cell apoptosis: a homeostatic mechanism operating in resolution of mesangial proliferative nephritis in vivo and induced by growth factor deprivation in vivo. J Clin Invest 1994; 94: 2105–2116.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Kriz W, Elger M, Mundel, P, Lemley KV. Structure-stabilizing forces in the glomerular tuft. J Am Soc Nephrol 1995; 5: 1731–1739.PubMedGoogle Scholar
  41. 41.
    Nagata M, Schärer K, Kriz W. Glomerular damage after uninephrectomy in young rats: I. Hypertrophy and distortion of capillary architecture. Kidney Int 1992; 42: 136–147.CrossRefPubMedGoogle Scholar
  42. 42.
    Kriz W. Progressive renal failure-inability of podocytes to replicate and the consequences for development of glomerulosclerosis. Nephrol Dial Transplant 1996; 11: 1738–1742.PubMedGoogle Scholar
  43. 43.
    Floege JF, Alpers CE, Sage EH, Pritzl P, Gordon K, Johnson RJ, Couser WG. Markers of complement dependent and complement independent glomerular visceral epithelial cell injury in vivo: expression of anti adhesive proteins and cytoskeletal changes. Lab Invest 1992; 67: 486–497.PubMedGoogle Scholar
  44. 44.
    Shankland SJ, Pippin J, Pichler R, Gordon KL, Gold L, Johnson RJ, Couser WG. Differential expression of transforming growth factor β isoforms and receptors in experimental membranous nephropathy. Kidney Int 1996; 50: 116–124.CrossRefPubMedGoogle Scholar
  45. 45.
    Shankland SJ, Floege J, Thomas SE, Nangaku M, Pippin J, Henne K, Hockenberry DM, Johnson RJ, Couser WG. Cyclin kinase inhibitors are increased during experimental membranous nephropathy: potential role in limiting glomerular epithelial cell proliferation in vivo. Kidney Int 1997; 52: 404–413.CrossRefPubMedGoogle Scholar
  46. 46.
    Shimizu A, Kitamura H, Masuda Y, Ishizaki M, Sugisaki Y, Yamanaka N. Rare glomerular capillary regeneration and subsequent capillary regression with endothelial cell apoptosis in progressive glomerulonephritis. Am J Pathol 1997; 151: 1231–1239.PubMedPubMedCentralGoogle Scholar
  47. 47.
    Purkerson ML, Hoffsten PE, Klahr S. Pathogenesis of the glomerulopathy associated with renal infarction in rats. Kidney Int 1976; 9; 407–417.CrossRefPubMedGoogle Scholar
  48. 48.
    Floege J, Alpers CE, Burns MW, Pritzl P, Gordon K, Couser W, Johnson RJ. Glomerular cells, extracellular matrix accumulation and the development of glomerulosclerosis in the remnant kidney model. Lab Invest 1992; 66: 485–497.PubMedGoogle Scholar
  49. 49.
    Pawluczyk IZ, Harris KP. Macrophages promote prosclerotic responses in cultured rat mesangial cells: a mechanism for the initiation of glomerulosclerosis. J Am Soc Nephrol 1997; 8: 1525–1536.PubMedGoogle Scholar
  50. 50.
    Bohle A, Mackensen-Haen S, Harolo G. Significance of tubulointerstitial changes in the renal cortex for the excretory function and concentration ability of the kidney: a morphometric contribution. Am J Nephrol 1987; 7: 421–433.CrossRefPubMedGoogle Scholar
  51. 51.
    Pichler R, Giachelli C, Young B, Alpers CE, Couser WG, Johnson RJ. The pathogenesis of tubulointerstitial disease associated with glomerulonephritis: the glomerular cytokine theory. Miner Electrolyte Metab 1995; 21: 317–327.PubMedGoogle Scholar
  52. 52.
    Morita Y, Nomura A, Yuzawa Y, Nishikawa K, Hotta N, Shimizu F, Matsuo S. The role of complement in the pathogenesis of tubulointerstitial lesions in rat mesangial proliferative glomerulonephritis. J Am Soc Nephrol 1997; 8: 1363–1372.PubMedGoogle Scholar
  53. 53.
    Nomura A, Morita Y, Maruyama S, Hotta N, Nadai M, Wang L, Hasegawa T, Matsuo S. Role of complement in acute tubulointerstitial injury of rats with aminonucleoside nephrosis. Am J Path 1997; 151: 539–547.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Eddy AA. Interstitial inflammation and fibrosis in rats with diet-induced hypercholesterolemia. Kidney Int 1996; 50: 1139–1149.CrossRefPubMedGoogle Scholar
  55. 55.
    Kliem V, Johnson RJ, Alpers CE, Yoshimura A, Couser WG, Koch KM, Floege J. Mechanisms involved in the pathogenesis of tubulointerstitial fibrosis in 5/6-nephrectomized rats. Kidney Int 1996; 49: 666–678.CrossRefPubMedGoogle Scholar
  56. 56.
    Thomas SE, Anderson S, Gordon KL, Oyama TT, Shankland SJ, Johnson RJ. Tubulointerstitial disease in aging: evidence for underlying peritubular capillary damage, a potential role for renal ischemia. J Am Soc Nephrol 1998; 9: 231–242.PubMedGoogle Scholar
  57. 57.
    Thomas SE, Andoh TF, Pichler RH, Shankland SJ, Couser WG, Bennett WM, Johnson RJ. Accelerated apoptosis characterizes cyclosporine-associated interstitial fibrosis. Kidney Int 1998; 53: 897–908.CrossRefPubMedGoogle Scholar
  58. 58.
    Ophascharoensuk V, Giachelli CM, Liaw L, Shankland SJ, Couser WG, Johnson RJ. Osteopontin (OPN) mediates early macrophage influx in ren al interstitial inflammation: a study in OPN knockout (KO) mice. J Am Soc Nephrol 1997; 8: 481A (abstr).Google Scholar
  59. 59.
    Rollo EE, Denhardt DT. Differential effect of osteopontin on the cytotoxic activity of macrophages from young and old mice. Immunology 1996; 88: 642–647.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Pichler RH, Hugo C, Shankland SJ, Reed MJ, Bassuk JA, Andoh TF, Lombardi DM, Schwartz SM, Bennett WM, Alpers CE, Sage EH, Johnson RJ, Couser WG. SPARC is expressed in renal interstitial fibrosis and in renal vascular injury. Kidney Int 1996; 50: 1978–1989.CrossRefPubMedGoogle Scholar
  61. 61.
    Alpers CE, Hudkins KL, Floege J, Johnson RJ. Human renal cortical interstitial cells with some features of smooth muscle cells participate in tubulointerstitial and crescentic glomerular injury. J Am Soc Nephrol 1994; 5: 201–210.PubMedGoogle Scholar
  62. 62.
    Tang WW, Ulich TR, Lacey DL, Hill DC, Qi M, Kaufman SA, Van GY, Tarpley JE, Yee JS. Platelet-derived growth factor-BB induces renal tubulointerstitial myofibroblast formation and tubulointerstitial fibrosis. Am J Pathol 1996; 148: 1169–1180.PubMedPubMedCentralGoogle Scholar
  63. 63.
    Eddy AA. Expression of genes that promote renal interstitial fibrosis in rats with proteinuria. Kidney Int 1996; 49: S49-S54.Google Scholar
  64. 64.
    Hugo C, Shankland SJ, Pichler RH, Couser WG, Johnson RJ. Thrombospondin 1 precedes and predicts the development of tubulointerstitial fibrosis in glomerular disease in the rat. Kidney Int 1998; 53: 302–311.CrossRefPubMedGoogle Scholar
  65. 65.
    Bohle A, Mackensen-Haen S, Wehrmann M. Significance of postglomerular capillaries in the pathogenesis of chronic renal failure. Kidney Blood Press Res 1996; 19: 191–195.CrossRefPubMedGoogle Scholar
  66. 66.
    Main IW, Nikolic-Paterson DJ, Atkins RC. T cells and macrophages and their role in renal injury. Semin Nephrol 1992; 12: 395–407.PubMedGoogle Scholar
  67. 67.
    Grandaliano G, Gesualdo L, Raniere E, Monno R, Montinaro V, Marra F, Schena FP. Monocyte chemotactic peptide-1 expression in acute and chronic human nephritides: a pathogenetic role in interstitial monocytes recruitment. J Am Soc Nephrol 1996; 7: 906–914.PubMedGoogle Scholar
  68. 68.
    Roy-Chaudhury P, Wu B, King G, Campbell M, MacLeod AM, Haites NE, Simpson JG, Power DA. Adhesion molecule interactions in human glomerulonephritis: importance of the tubulointersitium. Kidney Int 1996; 49: 127–134.CrossRefPubMedGoogle Scholar
  69. 69.
    Giachelli CM, Lombardi D, Johnson RJ, Murry CE, Almeida M. Evidence for a role of osteopontin in macrophage infiltration in response to pathological stimuli in vivo. Am J Pathol 1998; 152: 353–358.PubMedPubMedCentralGoogle Scholar
  70. 70.
    Pichler R, Giachelli CM, Lombardi D, Pippin J, Gordon K, Alpers CE, Schwartz S, Johnson RJ. Tubulointerstitial disease in glomerulonephritis: potential role of osteopontin (uropontin). Am J Pathol 1994; 144: 915–926.PubMedPubMedCentralGoogle Scholar
  71. 71.
    Pichler RH, Andoh TF, Hugo C, Shankland SJ, Nangaku M, Ophascharoensuk V, Giachelli C, Zachem C, Eng G, Alpers CE, Bennett WM, Couser WG, Johnson RJ. Differential expression of nitric oxide synthase (NOS) isoforms in CSA nephropathy: potential regulation by osteopontin (OPN). J Am Soc Nephrol 1996; 7: 1763 (abstr).Google Scholar
  72. 72.
    Yu XQ, Nikolic-Paterson DJ, Mu W, Giachelli CM, Atkins RC, Johnson RJ, Lan HY. A functional role for osteopontin in experimental crescentic glomerulonephritis in the rat. Proc Assoc Am Phys 1998; 110: 50–64.PubMedGoogle Scholar

Copyright information

© CEN/CLJ 1998

Authors and Affiliations

  • Richard J. Johnson
    • 1
  • Christian Hugo
    • 1
  • Leah Haseley
    • 1
  • Raimund Pichler
    • 1
  • James Bassuk
    • 1
  • Susan Thomas
    • 1
  • Shinichi Suga
    • 1
  • William G. Couser
    • 1
  • Stuart J. Shankland
    • 1
  1. 1.Division of NephrologyUniversity of Washington Medical CenterSeattleUSA

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