Loss of dicer exacerbates cyclophosphamide-induced bladder overactivity by enhancing purinergic signaling

Shu Zhang, Jian Wei Lv, Ping Yang, Qilin Yu, Junfeng Pang, Zhihua Wang, Hui Guo, Shenpei Liu, Jia Hu, Jiayi Li, Jin Leng, Yiran Huang, Zhangqun Ye, Cong Yi Wang

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)937-946
Number of pages10
JournalAmerican Journal of Pathology
Volume181
Issue number3
DOIs
StatePublished - Sep 1 2012

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Overactive Urinary Bladder
Cyclophosphamide
MicroRNAs
Urinary Bladder
Ribonuclease III
Messenger RNA
Urodynamics
Macrophages
Biopsy
Gene Expression

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Loss of dicer exacerbates cyclophosphamide-induced bladder overactivity by enhancing purinergic signaling. / Zhang, Shu; Lv, Jian Wei; Yang, Ping; Yu, Qilin; Pang, Junfeng; Wang, Zhihua; Guo, Hui; Liu, Shenpei; Hu, Jia; Li, Jiayi; Leng, Jin; Huang, Yiran; Ye, Zhangqun; Wang, Cong Yi.

In: American Journal of Pathology, Vol. 181, No. 3, 01.09.2012, p. 937-946.

Research output: Contribution to journalArticle

Zhang, S, Lv, JW, Yang, P, Yu, Q, Pang, J, Wang, Z, Guo, H, Liu, S, Hu, J, Li, J, Leng, J, Huang, Y, Ye, Z & Wang, CY 2012, 'Loss of dicer exacerbates cyclophosphamide-induced bladder overactivity by enhancing purinergic signaling', American Journal of Pathology, vol. 181, no. 3, pp. 937-946. https://doi.org/10.1016/j.ajpath.2012.05.035
Zhang, Shu ; Lv, Jian Wei ; Yang, Ping ; Yu, Qilin ; Pang, Junfeng ; Wang, Zhihua ; Guo, Hui ; Liu, Shenpei ; Hu, Jia ; Li, Jiayi ; Leng, Jin ; Huang, Yiran ; Ye, Zhangqun ; Wang, Cong Yi. / Loss of dicer exacerbates cyclophosphamide-induced bladder overactivity by enhancing purinergic signaling. In: American Journal of Pathology. 2012 ; Vol. 181, No. 3. pp. 937-946.
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