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Molecular mechanisms of bladder outlet obstruction in transgenic male mice overexpressing aromatase (Cyp19a1).

Authors: Lin, W  Rahman, NA  Lin, J  Zhang, H  Gou, K  Yu, W  Zhu, D  Li, N  Huhtaniemi, I  Li, X 
Citation: Lin W, etal., Am J Pathol. 2011 Mar;178(3):1233-44. doi: 10.1016/j.ajpath.2010.11.056.
Pubmed: (View Article at PubMed) PMID:21356374
DOI: Full-text: DOI:10.1016/j.ajpath.2010.11.056

We investigated the etiology and molecular mechanisms of bladder outlet obstruction (BOO). Transgenic (Tg) male mice overexpressing aromatase (Cyp19a1) under the ubiquitin C promoter in the estrogen-susceptible C57Bl/6J genetic background (AROM+/6J) developed inguinal hernia by 2 months and severe BOO by 9 to 10 months, with 100% penetrance. These mice gradually developed uremia, renal failure, renal retention, and finally died. The BOO bladders were threefold larger than in age-matched wild-type (WT) males and were filled with urine on necropsy. Hypotrophic smooth muscle cells formed the thin detrusor urinae muscle, and collagen III accumulation contributed to the reduced compliance of the bladder. p-AKT and ERalpha expression were up-regulated and Pten expression was down-regulated in the BOO bladder urothelium. Expression of only ERalpha in the intradetrusor fibroblasts suggests a specific role of this estrogen receptor form in urothelial proliferation. Inactivation of Pten, which in turn activated the p-AKT pathway, was strictly related to the activation of the ERalpha pathway in the BOO bladders. Human relevance for these findings was provided by increased expression of p-AKT, PCNA, and ERalpha and decreased expression of PTEN in severe human BOO samples, compared with subnormal to mild samples. These findings clarify the involvement of estrogen excess and/or imbalance of the androgen/estrogen ratio in the molecular pathogenetic mechanisms of BOO and provide a novel lead into potential treatment strategies for BOO.

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CRRD Object Information
CRRD ID: 7257709
Created: 2013-08-30
Species: All species
Last Modified: 2013-08-30
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.