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(American Journal of Pathology. 2000;157:1633-1647.)
© 2000 American Society for Investigative Pathology

Regular Articles

Potential Biological Role of Transforming Growth Factor-ß1 in Human Congenital Kidney Malformations

Su P. Yang^*, Adrian S. Woolf^*, Hai T. Yuan^*, Rosemary J. Scott, R. Anthony Risdon, Michael J. O’Hare^§ and Paul J. D. Winyard^*

From the Nephro-Urology^*
and Histopathology
Units, Institute of Child Health, the Histopathology Department,
and the Ludwig Institute for Cancer Research, University College London Breast Cancer Laboratory,^§
University College, London, United Kingdom

Transformations between epithelial and mesenchymal cells are widespread during normal development and adult disease, and transforming growth factor-ß1 (TGF-ß1) has been implicated in some of these phenotypic switches. Dysplastic kidneys are a common cause of chronic kidney failure in young children and result from perturbed epithelial-mesenchymal interactions. In this study, we found that components of the TGF-ß1 axis were expressed in these malformations: TGF-ß1 mRNA and protein were up-regulated in dysplastic epithelia and surrounding mesenchymal cells, whereas TGF-ß receptors I and II were expressed in aberrant epithelia. We generated a dysplastic kidney epithelial-like cell line that expressed cytokeratin, ZO1, and MET, and found that exogenous TGF-ß1 inhibited proliferation and decreased expression of PAX2 and BCL2, molecules characterizing dysplastic tubules in vivo. Furthermore, addition of TGF-ß1 specifically induced morphological changes compatible with a shift to a mesenchymal phenotype, accompanied by loss of ZO1 at cell borders and up-regulation of the mesenchymal markers -smooth muscle actin and fibronectin. The descriptive and functional data presented in this report potentially implicate TGF-ß1 in the pathobiology of dysplastic kidneys and our results provide preliminary evidence that an epithelial-to-mesenchymal phenotypic switch may be implicated in a clinically important developmental aberration.

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