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  • Title: Deregulation of renal transforming growth factor-beta1 after experimental short-term ureteric obstruction in fetal sheep.
    Author: Yang SP, Woolf AS, Quinn F, Winyard PJ.
    Journal: Am J Pathol; 2001 Jul; 159(1):109-17. PubMed ID: 11438459.
    Abstract:
    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-beta1 (TGF-beta1) occurs after experimental postnatal urinary tract obstruction and we recently reported increased levels of TGF-beta1 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-beta1, which then perturbs renal development. In this study, therefore, we examined expression of components of the TGF-beta1 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-beta1 mRNA and protein was observed in obstructed kidneys, compared to sham-operated control organs, after only 10 days. Increased levels of TGF-beta1 receptors I (TGF-betaR1) and II (TGF-betaR2) were also detected on Western blot, and the cytokine and TGF-betaR1 co-localized in disrupted epithelia on immunohistochemistry. De novo expression of alpha-smooth muscle actin, a structural protein up-regulated during TGF-beta1-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-beta1 signaling in the early biological changes generated by fetal urinary tract obstruction.
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