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Virchows Archiv

, Volume 447, Issue 5, pp 859–868 | Cite as

Transforming growth factor-β1 mediated up-regulation of lysyl oxidase in the kidneys of hereditary nephrotic mouse with chronic renal fibrosis

  • Yasufumi Goto
  • Kozue Uchio-Yamada
  • Sayuri Anan
  • Yoshie Yamamoto
  • Atsuo Ogura
  • Noboru ManabeEmail author
Original Article

Abstract

Lysyl oxidase (LOX), an extracellular emzyme, plays a key role in the post-translational modification of collagens and elastin, catalyzing inter- and intra-crosslinking reactions. Because the crosslinked extracellular matrices (ECMs) are highly resistant to degradative enzymes, it is considered that the over-expression of LOX may cause severe fibrotic degeneration. In the present study, we addressed the role of LOX-mediated crosslinking in chronic renal tubulointerstitial fibrosis using an animal model of hereditary nephrotic syndrome, the Institute of Cancer Research (ICR)-derived glomerulonephritis (ICGN) mouse. Ribonuclease protection assay (RPA) revealed that LOX mRNA expression was up-regulated in the kidneys of ICGN mice as compared with control ICR mice. High-level expression of LOX and transforming growth factor (TGF)-β1 (an up-regulator of LOX) mRNA was detected in tubular epithelial cells of ICGN mouse kidneys by in situ hybridization. Type-I and -III collagens, major substrates for LOX, were accumulated in tubulointerstitium of ICGN mouse kidneys. The present findings imply that TGF-β1 up-regulates the production of LOX in tubular epithelial cells of ICGN mouse kidneys, and the excessive LOX acts on interstitial collagens and catalyzes crosslinking reactions. As a result, the highly crosslinked collagens induce an irreversible progression of chronic renal tubulointerstitial fibrosis in the kidneys of ICGN mice.

Keywords

Extracellular matrix Lysyl oxidase Renal tubulointerstitial fibrosis Transforming growth factor-β1 

Notes

Acknowledgements

This work was supported by a Grant-in-Aid for Creative Scientific Research (13GS0008) to N.M. from the Ministry of Education, Culture, Sports, Science and Technology in Japan and by a Grant-in-Aid for Scientific Research (S) (16108003) to N.M. from the Japan Society for the Promotion of Science.

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Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Yasufumi Goto
    • 1
    • 2
  • Kozue Uchio-Yamada
    • 3
  • Sayuri Anan
    • 1
    • 2
  • Yoshie Yamamoto
    • 3
  • Atsuo Ogura
    • 4
  • Noboru Manabe
    • 1
    Email author
  1. 1.Research Unit for Animal Life Sciences, Animal Resource Science CenterThe University of TokyoIbaraki-IwamaJapan
  2. 2.Unit of Anatomy and Cell Biology, Department of Animal SciencesKyoto UniversityKyotoJapan
  3. 3.Department of Veterinary SciencesNational Institute of Infectious DiseasesTokyoJapan
  4. 4.Bioresource CenterRIKENTsukubaJapan

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