Inhibition of LIM kinase reduces contraction and proliferation in bladder smooth muscle

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 in vitro and in vivo 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 LIMK1 and LIMK2 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.

Serum response factor:Look into the gut

Serum response factor(SRF) is a transcription factor that regulates many genes involved in cellular activities such as proliferation,migration,differentiation,angiogenesis,and apoptosis.Although it has only been known for about two decades,SRF has been studied extensively.To date,over a thousand SRF studies have been published,but it still remains a hot topic.Due to its critical role in mesoderm-derived tissues,most of the SRF studies focused on muscle structure/function,cardiovascular development/maintenance,and smooth muscle generation/repair.Recently,SRF has received more attention in the digestive field and several important discoveries have been made.This review will summarize what we have learned about SRF in the gastrointestinal tract and provide insights into possible future directions in this area.