title: Deregulation of renal transforming growth factor-beta1 after experimental short-term ureteric obstruction in fetal sheep.
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.
authors: Nephro-Urology Unit, Institute of Child Health, University College London, United Kingdom.
authors: S P
authors: SP
authors: Yang
authors: A S
authors: AS
authors: Woolf
authors: F
authors: F
authors: Quinn
authors: P J
authors: PJ
authors: Winyard
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D005333:Fetus / Q000378:metabolism; D007150:Immunohistochemistry; D007668:Kidney / Q000196:embryology*; D009130:Muscle, Smooth / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D012016:Reference Values; D012756:Sheep / Q000196:embryology; D013997:Time Factors; D014018:Tissue Distribution; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation; D014517:Ureteral Obstruction / Q000196:embryology*
chemical_list: D000199:Actins; D020033:Protein Isoforms; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1