Potential biological role of transforming growth factor-beta 1 in human congenital kidney malformations

Transformations between epithelial and mesenchymal cells are widespread dur ing normal development and adult disease, and transforming growth factor-be ta1 (TGF-beta1) has been implicated in some of these phenotypic switches. D ysplastic kidneys are a common cause of chronic kidney failure in young chi ldren and result from perturbed epithelial-mesenchymal interactions. In thi s study, we found that components of the TGF-beta1 axis were expressed in t hese malformations: TGF-beta1 mRNA and protein were up-regulated In dysplas tic epithelia and surrounding mesenchymal cells, whereas TGF-beta receptors I and II were expressed in aberrant epithelia, We generated a dysplastic k idney epithelial-like cell line that expressed cytokeratin, ZO1, and MET, a nd found that exogenous TGF-beta1 inhibited proliferation and decreased exp ression of PAX2 and BCL2, molecules characterizing dysplastic tubules in vi tro, Furthermore, addition of TGF-beta1 specifically induced morphological changes compatible with a shift to a mesenchymal phenotype, accompanied by loss of ZO1 at cell borders and upregulation of the mesenchymal markers alp ha -smooth muscle actin and fibronectin, The descriptive and functional dat a presented in this report potentially implicate TGF-beta1 in the pathobiol ogy of dysplastic kidneys and our results provide preliminary evidence that an epithelial-to-mesenchymal phenotypic switch may be implicated in a clin ically Important developmental aberration.