TY - JOUR
T1 - Loss of dicer exacerbates cyclophosphamide-induced bladder overactivity by enhancing purinergic signaling
AU - Zhang, Shu
AU - Lv, Jian Wei
AU - Yang, Ping
AU - Yu, Qilin
AU - Pang, Junfeng
AU - Wang, Zhihua
AU - Guo, Hui
AU - Liu, Shenpei
AU - Hu, Jia
AU - Li, Jiayi
AU - Leng, Jin
AU - Huang, Yiran
AU - Ye, Zhangqun
AU - Wang, Cong Yi
N1 - Funding Information:
Supported by grants from the National Natural Science Foundation of China (Key Project Award 81130014 and Career Development Award 81100538 ), the European Foundation for the Study of Diabetes/Chinese Diabetes Society/Lilly Program for Collaborative Diabetes Research between China and Europe, and Bridge Funding from Tongji Hospital ( hgry201002 ).
PY - 2012/9
Y1 - 2012/9
N2 - microRNAs (miRNAs) have regulated the expression and function of genes implicated in many pathological settings, but their impact on the pathoetiological characteristics of overactive bladder (OAB) largely remains unknown. We have generated a mouse model in which adult mice can be induced for detrusor deletion of Dicer, an enzyme essential for miRNA processing. Targeted deletion of Dicer did not lead to a significant change for detrusor functionality under physiological conditions; however, loss of Dicer exacerbated cyclophosphamide-induced OAB, manifested by the higher severity of altered detrusor contractile force and sensitivity, abnormal urodynamics, and enhanced macrophage infiltration. Mechanistic studies revealed that loss of Dicer may impair the expression of miRNAs that are capable of targeting P2x mRNAs. As a result, mice deficient in Dicer manifest enhanced P2X expression in the detrusor on cyclophosphamide treatment, predisposing to the increased risk for OAB development. More important, studies using bladder biopsy samples of patients with OAB also demonstrated similar results as those found in animals. Taken together, our results suggest that miRNAs modulate OAB susceptibility by regulating purinergic signaling, in which the pathogenic insult induces the expression of miRNAs capable of targeting P2X mRNAs to suppress OAB symptoms.
AB - microRNAs (miRNAs) have regulated the expression and function of genes implicated in many pathological settings, but their impact on the pathoetiological characteristics of overactive bladder (OAB) largely remains unknown. We have generated a mouse model in which adult mice can be induced for detrusor deletion of Dicer, an enzyme essential for miRNA processing. Targeted deletion of Dicer did not lead to a significant change for detrusor functionality under physiological conditions; however, loss of Dicer exacerbated cyclophosphamide-induced OAB, manifested by the higher severity of altered detrusor contractile force and sensitivity, abnormal urodynamics, and enhanced macrophage infiltration. Mechanistic studies revealed that loss of Dicer may impair the expression of miRNAs that are capable of targeting P2x mRNAs. As a result, mice deficient in Dicer manifest enhanced P2X expression in the detrusor on cyclophosphamide treatment, predisposing to the increased risk for OAB development. More important, studies using bladder biopsy samples of patients with OAB also demonstrated similar results as those found in animals. Taken together, our results suggest that miRNAs modulate OAB susceptibility by regulating purinergic signaling, in which the pathogenic insult induces the expression of miRNAs capable of targeting P2X mRNAs to suppress OAB symptoms.
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U2 - 10.1016/j.ajpath.2012.05.035
DO - 10.1016/j.ajpath.2012.05.035
M3 - Article
C2 - 22796409
AN - SCOPUS:84865260656
SN - 0002-9440
VL - 181
SP - 937
EP - 946
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 3
ER -