Yu Qingfeng, Wu Chengjie, Chen Yeda, Li Bingsheng, Wang Ruixiao, Huang Ru, Li Xuechun, Gu Di, Wang Xiaolong, Duan Xiaolu, Li Shujue, Liu Yang, Wu Wenqi, Hennenberg Martin, Zeng Guohua
Department of Urology and Guangdong Key Laboratory of Urology, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510230, China.
Department of Urology, University Hospital, LMU Munich, Munich 81377, Germany.
Acta Pharm Sin B. 2021 Jul;11(7):1914-1930. doi: 10.1016/j.apsb.2021.01.005. Epub 2021 Jan 7.
Overactive bladder (OAB) is the most bothersome symptom in lower urinary tract symptoms (LUTS). Current pharmacologic treatment aims to inhibit detrusor contraction; however, shows unsatisfied efficacy and high discontinuation rate. LIM kinases (LIMKs) promote smooth muscle contraction in the prostate; however, their function in the bladder smooth muscle remains unclear. Here, we studied effects of the LIMK inhibitors on bladder smooth muscle contraction and proliferation both and experiments. Bladder expressions of LIMKs are elevated in OAB rat detrusor tissues. Two LIMK inhibitors, SR7826 and LIMKi3, inhibit contraction of human detrusor strip, and cause actin filament breakdown, as well as cell proliferation reduction in cultured human bladder smooth muscle cells (HBSMCs), paralleled by reduced cofilin phosphorylation. Silencing of and in HBSMCs resulted in breakdown of actin filaments and decreased cell proliferation. Treatment with SR7826 or LIMKi3 decreased micturition frequency and bladder detrusor hypertrophy in rats with bladder outlet obstruction. Our study suggests that LIMKs may promote contraction and proliferation in the bladder smooth muscle, which could be inhibited by small molecule LIMK inhibitors. LIMK inhibitors could be a potential therapeutic strategy for OAB- related LUTS.
膀胱过度活动症（OAB）是下尿路症状（LUTS）中最困扰人的症状。目前的药物治疗旨在抑制逼尿肌收缩；然而，其疗效并不理想且停药率高。LIM激酶（LIMKs）促进前列腺平滑肌收缩；然而，它们在膀胱平滑肌中的功能仍不清楚。在此，我们在体内和体外实验中研究了LIMK抑制剂对膀胱平滑肌收缩和增殖的影响。在OAB大鼠逼尿肌组织中，LIMKs的膀胱表达升高。两种LIMK抑制剂，SR7826和LIMKi3，抑制人逼尿肌条的收缩，并导致肌动蛋白丝断裂，以及培养的人膀胱平滑肌细胞（HBSMCs）增殖减少，同时伴肌动蛋白结合蛋白磷酸化减少。在HBSMCs中沉默LIMK1和LIMK2导致肌动蛋白丝断裂和细胞增殖减少。用SR7826或LIMKi3治疗可降低膀胱出口梗阻大鼠的排尿频率和膀胱逼尿肌肥大。我们的研究表明，LIMKs可能促进膀胱平滑肌的收缩和增殖，而小分子LIMK抑制剂可抑制这些作用。LIMK抑制剂可能是治疗与OAB相关的LUTS的一种潜在治疗策略。
