A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Molecular Mechanisms of Bladder Outlet Obstruction in Transgenic Male Mice Overexpressing Aromatase (Cyp19a1)
Tekijät: Lin W, Rahman NA, Lin JA, Zhang H, Gou KM, Yu WP, Zhu DH, Li N, Huhtaniemi I, Li XD
Kustantaja: ELSEVIER SCIENCE INC
Julkaisuvuosi: 2011
Journal: American Journal of Pathology
Tietokannassa oleva lehden nimi: AMERICAN JOURNAL OF PATHOLOGY
Lehden akronyymi: AM J PATHOL
Numero sarjassa: 3
Vuosikerta: 178
Numero: 3
Aloitussivu: 1233
Lopetussivu: 1244
Sivujen määrä: 12
ISSN: 0002-9440
DOI: https://doi.org/10.1016/j.ajpath.2010.11.056
Tiivistelmä
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 C57B1/6j 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 ER a expression were up-regulated and Pten expression was down-regulated in the BOO bladder urothelium. Expression of only ER alpha 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 ER a pathway in the BOO bladders. Human relevance for these findings was provided by increased expression of p-AKT, PCNA, and ER alpha 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. (Am J Pathol 2011, 178.1233-1244; 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 C57B1/6j 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 ER a expression were up-regulated and Pten expression was down-regulated in the BOO bladder urothelium. Expression of only ER alpha 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 ER a pathway in the BOO bladders. Human relevance for these findings was provided by increased expression of p-AKT, PCNA, and ER alpha 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. (Am J Pathol 2011, 178.1233-1244; DOI: 10.1016/j.ajpath.2010.11.056)
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