Structural and functional changes in gap junctional intercellular communication in a rat model of overactive bladder syndrome induced by partial bladder outlet obstruction

Abstract

The aim of the present study was to investigate the association between connexin (Cx)43 levels and alterations in gap junctional mediation of intercellular communication in overactive bladder syndrome (OAB), and to examine the effects of connexin inhibitor on this condition. Adult female Wistar rats with OAB following partial bladder outlet obstruction (PBBO) (OAB group, n=37) and sham-operated rats (control group, n=17) were studied. The ultrastructure of the rat detrusor was observed by transmission electron microscopy and the protein expression levels of Cx43 were analyzed using western blot analysis. Furthermore, bladder detrusor cells in both groups were cultured and cells in the OAB group were randomly divided into ten groups. In nine of these groups, 18-β glycyrrhetinic acid (18β-GA) was administered at various doses and durations. All groups were compared using fluorescence redistribution after photobleaching and a laser scanning confocal microscope. Cystometry demonstrated that gap junctions were an abundant mechanism among adjacent cells, and Cx43 protein expression levels were increased in the OAB group following 6 weeks of obstruction, as compared with the control group. Mean fluorescence recovery rates in the OAB group were significantly increased, as compared with the control group (P<0.01). Mean fluorescence recovery rates were noted following 18β-GA administration. These results suggested that upregulation of Cx43 induces structural and functional alterations in gap junctional intercellular communication following PBOO, and connexin inhibitors may be a novel therapeutic strategy for the clinical treatment of OAB.

Gene Therapy for Overactive Bladder: A Review of BK-Channel α-Subunit Gene Transfer

“…36 High levels of gap junction expression would likewise be expected to make the bladder smooth muscle cells hypersensitive to cholinergic stimulation, presumably due to excessive diffusion of Ca 2+ ions among detrusor coupled myocytes. 15,[37][38][39] Indeed, upregulation of connexin 43, a predominant connexin protein expressed in human bladder gap junctions, has been identified in patients with urgency incontinence. 32 The use of gene therapy to treat bladder dysfunction may have intrinsic advantages over conventional pharmacotherapies when the therapeutic target is subject to epigenetic modification.…”

Benefits and limitations of animal models in partial bladder outlet obstruction for translational research

“…Several studies have shown the mechanisms of gap junctional communication in the pBOO model . Upregulation of connexin 43 induces structural and functional changes after pBOO, so connexin inhibitors could be a novel therapeutic option for the treatment of OAB …”

“…Furthermore, pBOO upregulated the Rho‐associated kinase pathway . Upregulation of connexin 43 induces structural and functional alterations in gap junctional intercellular communication following pBOO . pBOO also changes immune responses.…”

Mechanosensitivity Is a Characteristic Feature of Cultured Suburothelial Interstitial Cells of the Human Bladder

“…Coupling between ICs, the urothelium, and detrusor smooth muscle cells is another important issue which determines the normal function of the bladder and is significantly altered in disease, as demonstrated in BOO [11][12][13][14][15][16], OAB [17,18], and IC/BPS [19]. Furthermore, cell culture studies showed that cytokines can control connexin (Cx)43 and Cx45 expression in bladder smooth muscle cells and interstitial cells [20][21][22].…”