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From the Nephro-Urology Unit, Institute of Child Health, University College London, United Kingdom
Renal malformations are the commonest cause of chronic renal
failure in children and they are often associated with urinary tract
abnormalities that impair fetal urine flow. Up-regulation of
transforming growth factor-ß1 (TGF-ß1) occurs after experimental
postnatal urinary tract obstruction and we recently reported increased
levels of TGF-ß1 in human renal malformations (Yang SP et al,
Am J Pathol 2000, 157:16331647). These findings led us
to propose that obstruction-induced stretch of developing renal
epithelia causes up-regulation of TGF-ß1, which then perturbs
renal development. In this study, therefore, we
examined expression of components of the TGF-ß1 signaling axis in a
previously characterized ovine model of fetal short-term urine flow
impairment in which complete unilateral ureteric obstruction was
induced at 90 days when a few layers of glomeruli had formed.
Up-regulation of TGF-ß1 mRNA and protein was observed in obstructed
kidneys, compared to sham-operated control organs,
after only 10 days. Increased levels of TGF-ß1 receptors I
(TGF-ßR1) and II (TGF-ßR2) were also detected on Western
blot, and the cytokine and TGF-ßR1 co-localized in disrupted
epithelia on immunohistochemistry. De novo expression of
-smooth muscle actin, a structural protein up-regulated
during TGF-ß1-induced phenotypic switching between human renal
dysplastic epithelial and mesenchymal lineages in
vitro, was also observed in these aberrant epithelia.
These findings implicate increased TGF-ß1 signaling in the
early biological changes generated by fetal urinary tract
obstruction.
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