Abstract for presentation at Australia and New Zealand Society of Nephrology Annual Scientific Conference

E-cadherin Is A Key Molecule mediating Tubular Epithelial-Mesenchymal Transition In Renal Fibrosis

  • Guoping Zheng, Australia
  • Dr James Lyons, Sydney Head & Neck Cancer Institute, Sydney Cancer Centre , University of Sydney, Australia
  • Dr Yiping Wang, Centre for Transplantation and Renal Research, the University of Sydney at Westmead Millennium Institute., Australia
  • Dr Danqing Min, Department of Endocrinology, University of Sydney, Australia
  • Mr Jason Coombes, University of Sydney at Westmead Millennium Institute, Australia
  • Prof David Harris, The University of Sydney at Westmead Millenium Institute, Australia

    • Tubular epithelial-to-mesenchymal transition (EMT) is a major cause of renal interstitial fibrosis. However, the mechanisms of tubular EMT in renal fibrosis remain largely unknown. E-cadherin, an epithelial marker, may serve as a signal transduction molecule through binding to beta-catenin, a transcription factor involved in EMT. We postulated that E-cadherin is a key molecule in tubular EMT, and disruption of E-cadherin by matrix metalloproteinase (MMP) is a key cause of kidney fibrosis through tubular EMT. Treatment of NRK52e (rat TEC) cells with recombinant MMP-3 (rMMP-3) and E-cadherin N-terminal Ab induced EMT as evidenced by morphological changes, reduced E-cadherin, transnuclear localization of beta-catenin and de novo a-SMA expression. Induction of EMT by rMMP-3 was abrogated by MMP inhibitor GM6001. An 80kD E-cadherin proteolytic fragment was found in rMMP-3 treatment medium. Forced expression of Ecadherin in NRK49f (rat fibroblast) cells caused mesenchymal-to-epithelial transition, evidenced by morphological changes, expression of E-cadherin, abrogation of a-SMA and sequestration of beta-catenin to cytoplasm membrane. rMMP-3 was capable of repressing E-cadherin promoter in NRK2e cells that can be abrogated by GM6001, but not by anti-TGF-beta1 antibody, while repression of E-cadherin promoter by TGF-beta1 was prevented by GM6001, indicating the induction of EMT by rMMP-3 is TGF-beta1-independent and that of TGF-beta1 is MMP-dependent. In renal cortex of rats with Adriamycin nephrosis, Ecadherin protein was downregulated while MMP-2, -9 and -3 were upregulated. In conclusion, E-cadherin appears to be a key molecule in tubular EMT and disruption of E-cadherin by MMPs may be a key cause of kidney fibrosis.

    Conference Organiser - ICMS Pty Ltd