Potential biological role of transforming growth factor-beta1 in human congenital kidney malformations.
Transformations between epithelial and mesenchymal cells are widespread during normal development and adult disease, and transforming growth factor-beta1 (TGF-beta1) 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-beta1 axis were expressed in these malformations: TGF-beta1 mRNA and protein were up-regulated in dysplastic epithelia and surrounding mesenchymal cells, whereas TGF-beta 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-beta1 inhibited proliferation and decreased expression of PAX2 and BCL2, molecules characterizing dysplastic tubules in vivo. 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 up-regulation of the mesenchymal markers alpha-smooth muscle actin and fibronectin. The descriptive and functional data presented in this report potentially implicate TGF-beta1 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.
Yang
S P
SP
Nephro-Urology, Institute of Child Health, the Ludwig Institute for Cancer Research, University College London Breast Cancer Laboratory, University College, London, United Kingdom.
Woolf
A S
AS
Yuan
H T
HT
Scott
R J
RJ
Risdon
R A
RA
O'Hare
M J
MJ
Winyard
P J
PJ
D002675:Child, Preschool; D000013:Congenital Abnormalities / Q000235:genetics / Q000473:pathology; D005333:Fetus; D015870:Gene Expression; D006801:Humans; D007223:Infant; D007668:Kidney / Q000002:abnormalities* / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D010641:Phenotype; D012016:Reference Values; D016212:Transforming Growth Factor beta / Q000494:pharmacology / Q000502:physiology*; D053773:Transforming Growth Factor beta1
C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1