| First Author | Kanasaki K | Year | 2013 |
| Journal | FASEB J | Volume | 27 |
| Issue | 5 | Pages | 1950-61 |
| PubMed ID | 23395910 | Mgi Jnum | J:197843 |
| Mgi Id | MGI:5494782 | Doi | 10.1096/fj.12-223404 |
| Citation | Kanasaki K, et al. (2013) Loss of beta1-integrin from urothelium results in overactive bladder and incontinence in mice: a mechanosensory rather than structural phenotype. FASEB J 27(5):1950-61 |
| abstractText | Bladder urothelium senses and communicates information about bladder fullness. However, the mechanoreceptors that respond to tissue stretch are poorly defined. Integrins are mechanotransducers in other tissues. Therefore, we eliminated beta1-integrin selectively in urothelium of mice using Cre-LoxP targeted gene deletion. beta1-Integrin localized to basal/intermediate urothelial cells by confocal microscopy. beta1-Integrin conditional-knockout (beta1-cKO) mice lacking urothelial beta1-integrin exhibited down-regulation and mislocalization of alpha3- and alpha5-integrins by immunohistochemistry but, surprisingly, had normal morphology, permeability, and transepithelial resistance when compared with Cre-negative littermate controls. beta1-cKO mice were incontinent, as judged by random urine leakage on filter paper (4-fold higher spotting, P<0.01; 2.5-fold higher urine area percentage, P<0.05). Urodynamic function assessed by cystometry revealed bladder overfilling with 80% longer intercontractile intervals (P<0.05) and detrusor hyperactivity (3-fold more prevoid contractions, P<0.05), but smooth muscle contractility remained intact. ATP secretion into the lumen was elevated (49 vs. 22 nM, P<0.05), indicating abnormal filling-induced purinergic signaling, and short-circuit currents (measured in Ussing chambers) revealed 2-fold higher stretch-activated ion channel conductances in response to hydrostatic pressure of 1 cmH2O (P<0.05). We conclude that loss of integrin signaling from urothelium results in incontinence and overactive bladder due to abnormal mechanotransduction; more broadly, our findings indicate that urothelium itself directly modulates voiding. |
