Home LiteratureArticle Details
PMID: 12057905 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Renal fibrosis. Extracellular matrix microenvironment regulates migratory behavior of activated tubular epithelial cells.

The American journal of pathology ·Vol. 160 ·No. 6 ·2002-06-00 ·Pages 2001-8

Zeisberg M, Maeshima Y, Mosterman B, Kalluri R

Abstract

During progression of chronic renal disease, qualitative and quantitative changes in the composition of tubular basement membranes (TBMs) and interstitial matrix occur. Transforming growth factor (TGF)-beta(1)-mediated activation of tubular epithelial cells (TECs) is speculated to be a key contributor to the progression of tubulointerstitial fibrosis. To further understand the pathogenesis associated with renal fibrosis, we developed an in vitro Boyden chamber system using renal basement membranes that partially mimics in vivo conditions of TECs during health and disease. Direct stimulation of TECs with TGF-beta(1)/epithelial growth factor results in an increased migratory capacity across bovine TBM preparations. This is associated with increased matrix metalloproteinase (MMP) production, namely MMP-2 and MMP-9. Indirect chemotactic stimulation by TGF-beta(1)/EGF or collagen type I was insufficient in inducing migration of untreated TECs across bovine TBM preparation, suggesting that basement membrane integrity and composition play an important role in protecting TECs from interstitial fibrotic stimuli. Additionally, neutralization of MMPs by COL-3 inhibitor dramatically decreases the capacity of TGF-beta(1)-stimulated TECs to migrate through bovine TBM preparation. Collectively, these results demonstrate that basement membrane structure, integrity, and composition play an important role in determining interstitial influences on TECs and subsequent impact on potential aberrant cell-matrix interactions.

MeSH Terms
Adult Animals Basement Membrane/pathology,physiology Cattle Cell Movement Cells, Cultured Chemotaxis Electrophoresis, Polyacrylamide Gel Epidermal Growth Factor/pharmacology Epithelial Cells/cytology Extracellular Matrix/pathology,physiology Fibrosis/pathology Humans Kidney Failure, Chronic/pathology Kidney Tubules/cytology,pathology Matrix Metalloproteinase 2/metabolism Matrix Metalloproteinase 9/metabolism Mice Rabbits Transforming Growth Factor beta/pharmacology Transforming Growth Factor beta1
Chemicals
TGFB1 protein, human Tgfb1 protein, mouse Transforming Growth Factor beta Transforming Growth Factor beta1 Epidermal Growth Factor Matrix Metalloproteinase 2 Matrix Metalloproteinase 9
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Zeisberg Michael
Department of Medicine and the Liver Center, Program in Matrix Biology, Renal, and Gastroenterology Divisions, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
Maeshima Yohei
Mosterman Barbara
Kalluri Raghu
References (51)
51 references, click to expand
  1. Integrin alpha1beta1 and transforming growth factor-beta1 play distinct roles in alport glomerular pathogenesis and serve as dual targets for metabolic therapy.
    Am J Pathol. 2000 Nov;157(5):1649-59 PMID: 11073824
  2. Large scale preparation of bovine renal glomerular basement membrane in the presence of protease inhibitors.
    Prep Biochem. 1978;8(2-3):215-24 PMID: 568787
  3. The importance of tubulointerstitial damage in progressive renal disease.
    Nephrol Dial Transplant. 2000;15 Suppl 6:76-7 PMID: 11144000
  4. The role of the interstitium of the renal cortex in renal disease.
    Contrib Nephrol. 1979;16:109-14 PMID: 467060
  5. Cell-mediated immunity in interstitial nephritis. III. T lymphocyte-mediated fibroblast proliferation and collagen synthesis: an immune mechanism for renal fibrogenesis.
    J Immunol. 1980 Oct;125(4):1708-14 PMID: 6967914
  6. Murine interstitial nephritis. II. The adoptive transfer of disease with immune T lymphocytes produces a phenotypically complex interstitial lesion.
    J Immunol. 1984 Jul;133(1):234-9 PMID: 6144709
  7. Structure and biological activity of basement membrane proteins.
    Eur J Biochem. 1989 Apr 1;180(3):487-502 PMID: 2653817
  8. Assembly of basement membranes.
    Ann N Y Acad Sci. 1990;580:195-213 PMID: 2186690
  9. Suppression of experimental glomerulonephritis by antiserum against transforming growth factor beta 1.
    Nature. 1990 Jul 26;346(6282):371-4 PMID: 2374609
  10. Glomerular basement membrane. Identification of dimeric subunits of the noncollagenous domain (hexamer) of collagen IV and the Goodpasture antigen.
    J Biol Chem. 1991 Aug 15;266(23):15318-24 PMID: 1869555
  11. Goodpasture syndrome. Localization of the epitope for the autoantibodies to the carboxyl-terminal region of the alpha 3(IV) chain of basement membrane collagen.
    J Biol Chem. 1991 Dec 15;266(35):24018-24 PMID: 1721062
  12. Epithelial-mesenchymal transitions in development and tumor progression.
    EXS. 1995;74:1-15 PMID: 8527890
  13. An overview of epithelio-mesenchymal transformation.
    Acta Anat (Basel). 1995;154(1):8-20 PMID: 8714286
  14. Transforming growth factor-beta modulation of the alpha 1(IV) collagen gene in murine proximal tubular cells.
    Am J Physiol. 1996 Jul;271(1 Pt 2):F120-5 PMID: 8760252
  15. Transdifferentiation: a new angle on renal fibrosis.
    Exp Nephrol. 1996 Sep-Oct;4(5):267-70 PMID: 8931981
  16. Macromolecular organization of basement membranes.
    Curr Opin Cell Biol. 1996 Oct;8(5):618-24 PMID: 8939648
  17. Molecular insights into renal interstitial fibrosis.
    J Am Soc Nephrol. 1996 Dec;7(12):2495-508 PMID: 8989727
  18. Isoform switching of type IV collagen is developmentally arrested in X-linked Alport syndrome leading to increased susceptibility of renal basement membranes to endoproteolysis.
    J Clin Invest. 1997 May 15;99(10):2470-8 PMID: 9153291
  19. Expression of type IV collagen alpha1(IV)-alpha6(IV) polypeptides in normal and developing human kidney and in renal cell carcinomas and oncocytomas.
    Int J Cancer. 1997 Jul 3;72(1):43-9 PMID: 9212221
  20. Nonenzymatic glycation of type IV collagen and matrix metalloproteinase susceptibility.
    Kidney Int. 1997 Nov;52(5):1302-12 PMID: 9350653
  21. Early role of Fsp1 in epithelial-mesenchymal transformation.
    Am J Physiol. 1997 Oct;273(4 Pt 2):F563-74 PMID: 9362334
  22. Proximal tubular basement membrane width in insulin-dependent diabetes mellitus.
    Kidney Int. 1998 Mar;53(3):754-61 PMID: 9507223
  23. Structure and biological activity of the extracellular matrix.
    J Mol Med (Berl). 1998 Mar;76(3-4):253-65 PMID: 9535559
  24. Chemically modified tetracyclines inhibit human melanoma cell invasion and metastasis.
    Clin Exp Metastasis. 1998 Apr;16(3):217-25 PMID: 9568639
  25. Integrin alpha1beta1 mediates a unique collagen-dependent proliferation pathway in vivo.
    J Cell Biol. 1998 Jul 27;142(2):587-94 PMID: 9679154
  26. Tubular epithelial-myofibroblast transdifferentiation in progressive tubulointerstitial fibrosis in 5/6 nephrectomized rats.
    Kidney Int. 1998 Sep;54(3):864-76 PMID: 9734611
  27. Pathophysiology of progressive nephropathies.
    N Engl J Med. 1998 Nov 12;339(20):1448-56 PMID: 9811921
  28. Characteristic matrix and tubular basement membrane abnormalities in the CBA/Ca-kdkd mouse model of hereditary tubulointerstitial disease.
    Nephron. 1998 Nov;80(3):305-13 PMID: 9807040
  29. Absence of integrin alpha1beta1 in the mouse causes loss of feedback regulation of collagen synthesis in normal and wounded dermis.
    J Cell Sci. 1999 Feb;112 ( Pt 3):263-72 PMID: 9885280
  30. Unique changes in interstitial extracellular matrix composition are associated with rejection and cyclosporine toxicity in human renal allograft biopsies.
    Am J Kidney Dis. 1999 Jan;33(1):11-20 PMID: 9915262
  31. Tetracycline-based MMP inhibitors can prevent fibroblast-mediated collagen gel contraction in vitro.
    Adv Dent Res. 1998 Nov;12(2):86-93 PMID: 9972128
  32. Transforming growth factor-beta regulates tubular epithelial-myofibroblast transdifferentiation in vitro.
    Kidney Int. 1999 Oct;56(4):1455-67 PMID: 10504497
  33. Transformations between epithelium and mesenchyme: normal, pathological, and experimentally induced.
    Am J Kidney Dis. 1995 Oct;26(4):678-90 PMID: 7573028
  34. Renal basement membrane components.
    Kidney Int. 1999 Dec;56(6):2016-24 PMID: 10594777
  35. Assembly of type IV collagen. Insights from alpha3(IV) collagen-deficient mice.
    J Biol Chem. 2000 Apr 28;275(17):12719-24 PMID: 10777566
  36. Targeted expression of a dominant-negative EGF-R in the kidney reduces tubulo-interstitial lesions after renal injury.
    J Clin Invest. 2000 Jul;106(2):225-34 PMID: 10903338
  37. Anoikis.
    Methods Enzymol. 2000;322:472-9 PMID: 10914040
  38. Integrins in kidney development, function, and disease.
    Am J Physiol Renal Physiol. 2000 Aug;279(2):F233-42 PMID: 10919841
  39. Matrix metalloproteinases: effectors of development and normal physiology.
    Genes Dev. 2000 Sep 1;14(17):2123-33 PMID: 10970876
  40. Still more complexity in mammalian basement membranes.
    J Histochem Cytochem. 2000 Oct;48(10):1291-306 PMID: 10990484
  41. Transdifferentiation comes of age.
    Nephrol Dial Transplant. 2000 Nov;15(11):1729-31 PMID: 11071953
  42. Basement membrane proteins: structure, assembly, and cellular interactions.
    Crit Rev Biochem Mol Biol. 1992;27(1-2):93-127 PMID: 1309319
  43. Tumor cell interactions with the extracellular matrix during invasion and metastasis.
    Annu Rev Cell Biol. 1993;9:541-73 PMID: 8280471
  44. Transforming growth factor beta in tissue fibrosis.
    N Engl J Med. 1994 Nov 10;331(19):1286-92 PMID: 7935686
  45. Expression of beta 1 integrins changes during transformation of avian lens epithelium to mesenchyme in collagen gels.
    Dev Dyn. 1994 Dec;201(4):378-93 PMID: 7534501
  46. On the progression of chronic renal disease.
    Nephron. 1995;69(4):371-9 PMID: 7777099
  47. Identification and characterization of a fibroblast marker: FSP1.
    J Cell Biol. 1995 Jul;130(2):393-405 PMID: 7615639
  48. Renal fibrosis: an update.
    Curr Opin Nephrol Hypertens. 2001 May;10(3):315-20 PMID: 11342792
  49. Transforming growth factor-beta, basement membrane, and epithelial-mesenchymal transdifferentiation: implications for fibrosis in kidney disease.
    Am J Pathol. 2001 Oct;159(4):1187-92 PMID: 11583944
  50. Renal fibrosis: collagen composition and assembly regulates epithelial-mesenchymal transdifferentiation.
    Am J Pathol. 2001 Oct;159(4):1313-21 PMID: 11583959
  51. Epithelial-mesenchymal transformation of renal tubular epithelial cells in vitro and in vivo.
    Nephrol Dial Transplant. 2000;15 Suppl 6:44-6 PMID: 11143987
Article Info
Journal
The American journal of pathology
Abbr.
Am J Pathol
ISSN
0002-9440
DOI
10.1016/S0002-9440(10)61150-9
Published
2002-06-00
Pages
2001-8
Language
English
Region
United States
NLM ID
0370502
PMCID
PMC1850832
Subset
IM
Grants
NIDDK NIH HHS · R01 DK055001 · United States
NIDDK NIH HHS · DK51711 · United States
NIDDK NIH HHS · DK55001 · United States
External Links
PubMed source DOI: 10.1016/S0002-9440(10)61150-9 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2