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Up-regulation of Transforming Growth Factor-β and the Counter-regulatory Effects of Hepatocyte Growth Factor in Fetal Sheep Bladder Outlet Obstruction
Nora G. Lee1, Hao Fan2, Craig A. Peters3
1Boston University Medical Center, Boston, MA;2University of Virginia, Charlottesville, VA;3Children's National Medical Center, Washington, DC
Obstructive nephropathy is a major cause of renal insufficiency in children. Transforming growth factor-β1 (TGF-β1) plays a central role in the pathogenesis of obstructive renal injury. Hepatocyte growth factor (HGF) has been found to reduce fibrosis and tissue injury, but its relationship to TGF-β1 is less defined. We hypothesize that renal TGF-β will be increased in a fetal sheep model of bladder outlet obstruction (BOO) with a coordinate and compensatory increase in HGF.
Materials & Methods:
Six fetal sheep underwent partial BOO at 95 days gestation via a metal urethral ring and urachal ligation. These and four age-matched controls were sacrificed at 135 days gestation (term). Kidneys were retrieved, drained, and weighed. Formalin-fixed mid-sagittal kidney sections were obtained. Immunohistochemical localization of TGF-β1, TGF-β receptor type2 (TGF-βR2), and HGF was performed and quantified morphometrically.
Obstructed kidneys showed significantly greater TGF-β1 and TGF-βR2 staining compared to controls (p=0.048 and p=0.026 respectively). TGF-β1 was largely localized to tubules and moderately to the interstitium, whereas TGF-βR2 staining was heavily localized to tubules. HGF staining in obstructed kidneys was significantly greater than in controls (p=0.017), and localized to tubules and less so to the interstitium.
TGF-β1 and TGF-βR2 are up-regulated in sheep subjected to BOO with predominantly tubular presence. HGF is coordinately up-regulated and co-localized, likely as a compensatory mechanism to counteract effects of TGF-β1. HGF appears to be an important co-factor in the pathophysiology of congenital obstructive nephropathy and may be useful diagnostically and therapeutically in preventing/attenuating renal injury.
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