Skip to main content
SpringerLink
Log in

Dog as model for down-expression of E-cadherin and β-catenin in tubular epithelial cells in renal fibrosis

  • Original Article
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract

Mechanism of renal fibrosis leading to end stage kidney remains still a challenge of interest in humans. The pathogenesis of chronic kidney disease is characterized by progressive loss of kidney function and fibrosis. The mechanism of epithelial–mesenchymal transition (EMT) has been predominantly studied in in vitro studies, and we previously demonstrated the EMT of tubular epithelial cells in dogs. In this study, we examined and quantified the modifications of cadherin–catenin complex by immunohistochemistry of E-cadherin and β-catenin and the mesenchymal marker vimentin in 25 dogs with three different spontaneous inflammatory renal diseases. Results showed a significant down-expression of levels of E-cadherin and β-catenin directly correlated with the tubular–interstitial damage (TID). In TID grades 2 and 3, E-cadherin expression was significantly reduced (p < 0.001). β-catenin expression was overall similar to E-cadherin. The mesenchymal-associated protein, vimentin, was de novo identified in tubules within areas of inflammation. In this work, we identified the loss of cadherin or catenin expression as a progressive mechanism in tubulo-interstitial fibrosis, which allows dissociation of structural integrity of renal epithelia and loss of epithelial polarity. The dog might result more significant as model for new therapies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Aresu L, Rastaldi MP, Scanziani E, Baily J, Radaelli E, Pregel P, Valenza F (2007) Epithelial-mesenchymal transition (EMT) of renal tubular cells in canine glomerulonephritis. Virchows Arch 451:937–942

    Article  PubMed  CAS  Google Scholar 

  2. Blanco D, Vicent S, Elizegi E, Pino I, Fraga MF, Esteller M, Saffiotti U, Lecanda F, Montuenga LM (2004) Altered expression of adhesion molecules and epithelial-mesenchymal transition in silica-induced rat lung carcinogenesis. Lab Invest 84:999–1012

    Article  PubMed  CAS  Google Scholar 

  3. Bottinger EP (2007) TGF-beta in renal injury and disease. Semin Nephrol 27:309–320

    Article  PubMed  CAS  Google Scholar 

  4. Brunetti B, Sarli G, Preziosi R, Monari I, Benazzi C (2005) E-cadherin and beta-catenin reduction influence invasion but not proliferation and survival in canine malignant mammary tumors. Vet Pathol 42:781–787

    Article  PubMed  CAS  Google Scholar 

  5. Bush KT, Tsukamoto T, Nigam SK (2000) Selective degradation of E-cadherin and dissolution of E-cadherin-catenin complexes in epithelial ischemia. Am J Physiol Renal Physiol 278:F847–F852

    PubMed  CAS  Google Scholar 

  6. Capaldo CT, Macara IG (2007) Depletion of E-cadherin disrupts establishment but not maintenance of cell junctions in Madin-Darby canine kidney epithelial cells. Mol Biol Cell 18:189–200

    Article  PubMed  CAS  Google Scholar 

  7. Chen H, Paradies NE, Fedor-Chaiken M, Brackenbury R (1997) E-cadherin mediates adhesion and suppresses cell motility via distinct mechanisms. J Cell Sci 110:345–356

    PubMed  CAS  Google Scholar 

  8. Cho EA, Patterson LT, Brookhiser WT, Mah S, Kintner C, Dressler GR (1998) Differential expression and function of cadherin-6 during renal epithelium development. Development 125:803–812

    PubMed  CAS  Google Scholar 

  9. Conacci-Sorrell M, Simcha I, Ben-Yedidia T, Blechman J, Savagner P, Ben-Ze’ev A (2003) Autoregulation of E-cadherin expression by cadherin-cadherin interactions: the roles of beta-catenin signaling, Slug, and MAPK. J Cell Biol 163:847–857

    Article  PubMed  CAS  Google Scholar 

  10. Gupta S, Clarkson MR, Duggan J, Brady HR (2000) Connective tissue growth factor: potential role in glomerulosclerosis and tubulointerstitial fibrosis. Kidney Int 58:1389–1399

    Article  PubMed  CAS  Google Scholar 

  11. Hayashida Y, Honda K, Idogawa M, Ino Y, Ono M, Tsuchida A, Aoki T, Hirohashi S, Yamada T (2005) E-cadherin regulates the association between beta-catenin and actinin-4. Cancer Res 65:8836–8845

    Article  PubMed  CAS  Google Scholar 

  12. Hertig A, Verine J, Mougenot B, Jouanneau C, Ouali N, Sebe P, Glotz D, Ancel PY, Rondeau E, Xu-Dubois YC (2006) Risk factors for early epithelial to mesenchymal transition in renal grafts. Am J Transplant 6:2937–2946

    Article  PubMed  CAS  Google Scholar 

  13. Hirohashi S, Kanai Y (2003) E-cadherin mediates adhesion and suppresses cell motility via distinct mechanisms. Cancer Sci 110:345–356

    Google Scholar 

  14. Jinde K, Nikolic-Paterson DJ, Huang XR, Sakai H, Kurokawa K, Atkins RC, Lan HY (2001) Tubular phenotypic change in progressive tubulointerstitial fibrosis in human glomerulonephritis. Am J Kidney Dis 38:761–769

    Article  PubMed  CAS  Google Scholar 

  15. Kalluri R, Neilson EG (2003) Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest 112:1776–1784

    PubMed  CAS  Google Scholar 

  16. Kirchner T, Brabletz T (2000) Patterning and nuclear beta-catenin expression in the colonic adenoma-carcinoma sequence. Analogies with embryonic gastrulation. Am J Pathol 157:1113–1121

    PubMed  CAS  Google Scholar 

  17. Kitagawa T, Matsumoto K, Nagafuchi A, Tsukita S, Suzuki H (1999) Co-expression of E-cadherin and alpha-catenin molecules in colorectal cancer. Surg Today 29:511–518

    Article  PubMed  CAS  Google Scholar 

  18. Kreidberg JA, Symons JM (2000) Integrins in kidney development, function, and disease. Am J Physiol Renal Physiol 279:F233–F242

    PubMed  CAS  Google Scholar 

  19. Kwak JM, Min BW, Lee JH, Choi JS, Lee SI, Park SS, Kim J, Um JW, Kim SH, Moon HY (2007) The Prognostic Significance of E-Cadherin and Liver Intestine-Cadherin Expression in Colorectal Cancer. Dis Colon Rectum 50:1873–1880

    Article  PubMed  Google Scholar 

  20. Lee DB, Huang E, Ward HJ (2006) Tight junction biology and kidney dysfunction. Am J Physiol Renal Physiol 290:F20–F34

    Article  PubMed  CAS  Google Scholar 

  21. Lee JM, Dedhar S, Kalluri R, Thompson EW (2006) The epithelial-mesenchymal transition: new insights in signalling, development, and disease. J Cell Biol 172:973–981

    Article  PubMed  CAS  Google Scholar 

  22. Liu Y (2004) Epithelial to mesenchymal transition in renal fibrogenesis: pathologic significance, molecular mechanism, and therapeutic intervention. J Am Soc Nephrol 15:1–12

    Article  PubMed  CAS  Google Scholar 

  23. Masszi A, Fan L, Rosivall L, McCulloch CA, Rotstein OD, Mucsi I, Kapus A (2004) Integrity of cell-cell contacts is a critical regulator of TGF-beta 1-induced epithelial-to-myofibroblast transition: role for beta-catenin. Am J Pathol 165:1955–1967

    PubMed  CAS  Google Scholar 

  24. Nakajima S, Doi R, Toyoda E, Tsuji S, Wada M, Koizumi M, Tulachan SS, Ito D, Kami K, Mori T, Kawaguchi Y, Fujimoto K, Hosotani R, Imamura M (2004) N-cadherin expression and epithelial-mesenchymal transition in pancreatic carcinoma. Clin Cancer Res 10:4125–4133

    Article  PubMed  CAS  Google Scholar 

  25. Piepenhagen PA, Nelson WJ (1995) Differential expression of cell-cell and cell-substratum adhesion proteins along the kidney nephron. Am J Physiol 269:C1433–C1449

    PubMed  CAS  Google Scholar 

  26. Prozialeck WC, Edwards JR (2007) Cell adhesion molecules in chemically-induced renal injury. Pharmacol Ther 114:74–93

    Article  PubMed  CAS  Google Scholar 

  27. Rastaldi MP, Ferrario F, Giardino L, Dell’Antonio G, Grillo C, Grillo P, Strutz F, Müller GA, Colasanti G, D’Amico G (2002) Epithelial-mesenchymal transition of tubular epithelial cells in human renal biopsies. Kidney Int 62:137–146

    Article  PubMed  Google Scholar 

  28. Tepass U, Truong K, Godt D, Ikura M, Peifer M (2000) Cadherins in embryonic and neural morphogenesis. Nat Rev Mol Cell Biol 1:91–100

    Article  PubMed  CAS  Google Scholar 

  29. Tian YC, Fraser D, Attisano L, Phillips AO (2003) TGF-beta1-mediated alterations of renal proximal tubular epithelial cell phenotype. Am J Physiol Renal Physiol 285:F130–F142

    PubMed  CAS  Google Scholar 

  30. van Timmeren MM, van den Heuvel MC, Bailly V, Bakker SJ, van Goor H, Stegeman CA (2007) Tubular kidney injury molecule-1 (KIM-1) in human renal disease. J Pathol 212:209–217

    Article  PubMed  Google Scholar 

  31. Yang J, Liu Y (2001) Dissection of key events in tubular epithelial to myofibroblast transition and its implications in renal interstitial fibrosis. Am J Pathol 159:1465–1475

    PubMed  CAS  Google Scholar 

  32. Zeisberg M, Bonner G, Maeshima Y, Colorado P, Müller GA, Strutz F, Kalluri R (2001) Renal fibrosis: collagen composition and assembly regulates epithelial-mesenchymal transdifferentiation. Am J Pathol 159:1313–1321

    PubMed  CAS  Google Scholar 

Download references

Conflict of interest statement

We declare that we have no conflict of interest.

Author information

Authors and Affiliations

  1. Dipartimento di Patologia Animale, Facoltà di Medicina Veterinaria, Università degli studi di Torino, Via L. da Vinci 44, 10095, Grugliasco, TO, Italy

    Paola Pregel & Federico Valenza

  2. Renal Research Laboratory, Fondazione IRCCS, Milano, Italy

    Maria Pia Rastaldi

  3. Dipartimento di Patologia Animale, Igiene e Sanità Pubblica Veterinaria, Università degli Studi di Milano, Milano, Italy

    Enrico Radaelli & Eugenio Scanziani

  4. Dipartimento di Sanità Pubblica, Patologia Comparata e Igiene Veterinaria, Facoltà di Medicina Veterinaria, Università degli Studi di Padova, Agripolis, Padova, Italy

    Luca Aresu & Massimo Castagnaro

Authors
  1. Luca Aresu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maria Pia Rastaldi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paola Pregel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Federico Valenza
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Enrico Radaelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Eugenio Scanziani
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Massimo Castagnaro
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Luca Aresu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Aresu, L., Rastaldi, M.P., Pregel, P. et al. Dog as model for down-expression of E-cadherin and β-catenin in tubular epithelial cells in renal fibrosis. Virchows Arch 453, 617–625 (2008). https://doi.org/10.1007/s00428-008-0684-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-008-0684-8

Keywords

Search

Navigation