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(American Journal of Pathology. 2001;159:109-117.)
© 2001 American Society for Investigative Pathology


Regular Articles

Deregulation of Renal Transforming Growth Factor-ß1 after Experimental Short-Term Ureteric Obstruction in Fetal Sheep

Su P. Yang, Adrian S. Woolf, Feargal Quinn and Paul J. D. Winyard

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, 157:1633–1647). 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 {alpha}-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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