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(American Journal of Pathology. 2003;162:1271-1282.)
© 2003 American Society for Investigative Pathology

Urinary Outflow Obstruction Increases Apoptosis and Deregulates Bcl-2 and Bax Expression in the Fetal Ovine Bladder

Nikesh Thiruchelvam^*, Peter Nyirady^*, Donald M. Peebles, Christopher H. Fry, Peter M. Cuckow^* and Adrian S. Woolf^*

From the Nephro-Urology Unit, Institute of Child Health,^* Department of Obstetric & Gynaecology, and Division of Applied Physiology, Institute of Urology & Nephrology, University College London, London, United Kingdom

During organogenesis, net growth of tissues is determined by a balance between proliferation, hypertrophy, and apoptotic death. Human fetal bladder outflow obstruction is a major cause of end-stage renal failure in children and is associated with complex pathology in the kidney and lower urinary tract. Experimental manipulation of the fetal sheep urinary tract has proved informative in understanding the pathobiology of congenital obstructive uropathy. In this study we used an ovine model of fetal bladder outflow obstruction to examine effects on apoptotic cell death in the developing urinary bladder. While 30 days of obstruction in utero between 75 and 105 days gestation resulted in overall growth of the fetal bladder as assessed by weight, protein, and DNA measurements, we found that apoptosis, as assessed by in situ end-labeling, was up-regulated in fetal bladder detrusor muscle and lamina propria cells and that this was accompanied by a down-regulation of the anti-death protein Bcl-2 and an up-regulation of the pro-death protein Bax. Moreover, activated caspase-3, an effector of apoptotic death, was increased in obstructed bladders. This is the first study to define altered death in an experimental fetal model of bladder dysmorphogenesis. We speculate that enhanced apoptosis in detrusor smooth muscle cells is part of a remodeling response during compensatory hyperplasia and hypertrophy. Conversely, in the lamina propria, an imbalance between death and proliferation leads to a relative depletion of cells.

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