title: Molecular mechanisms of bladder outlet obstruction in transgenic male mice overexpressing aromatase (Cyp19a1).
abstract: 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 ERα expression were up-regulated and Pten expression was down-regulated in the BOO bladder urothelium. Expression of only ERα 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 ERα pathway in the BOO bladders. Human relevance for these findings was provided by increased expression of p-AKT, PCNA, and ERα 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.
authors.affiliation: State Key Laboratory for Agro-Biotechnology, Faculty of Biological Sciences, China Agricultural University, Beijing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Lin
authors.forename: Nafis A
authors.initials: NA
authors.lastname: Rahman
authors.forename: Jian
authors.initials: J
authors.lastname: Lin
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Kemian
authors.initials: K
authors.lastname: Gou
authors.forename: Wanpeng
authors.initials: W
authors.lastname: Yu
authors.forename: Dahai
authors.initials: D
authors.lastname: Zhu
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.forename: Ilpo
authors.initials: I
authors.lastname: Huhtaniemi
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Li
mesh_terms: D000368:Aged; D000818:Animals; D001141:Aromatase / Q000235:genetics / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D010641:Phenotype; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D001743:Urinary Bladder / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D001748:Urinary Bladder Neck Obstruction / Q000201:enzymology* / Q000473:pathology*
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D001141:Aromatase; D051057:Proto-Oncogene Proteins c-akt