title: Loss of β1-integrin from urothelium results in overactive bladder and incontinence in mice: a mechanosensory rather than structural phenotype.
abstract: 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 β1-integrin selectively in urothelium of mice using Cre-LoxP targeted gene deletion. β1-Integrin localized to basal/intermediate urothelial cells by confocal microscopy. β1-Integrin conditional-knockout (β1-cKO) mice lacking urothelial β1-integrin exhibited down-regulation and mislocalization of α3- and α5-integrins by immunohistochemistry but, surprisingly, had normal morphology, permeability, and transepithelial resistance when compared with Cre-negative littermate controls. β1-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.
authors: Division of Matrix Biology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
authors: Keizo
authors: K
authors: Kanasaki
authors: Weiqun
authors: W
authors: Yu
authors: Maximilian
authors: M
authors: von Bodungen
authors: John D
authors: JD
authors: Larigakis
authors: Megumi
authors: M
authors: Kanasaki
authors: Francisco
authors: F
authors: Ayala de la Pena
authors: Raghu
authors: R
authors: Kalluri
authors: Warren G
authors: WG
authors: Hill
mesh_terms: D000818:Animals; D015536:Down-Regulation; D019012:Integrin beta1 / Q000235:genetics*; D008297:Male; D040542:Mechanotransduction, Cellular / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D001743:Urinary Bladder / Q000503:physiopathology; D053201:Urinary Bladder, Overactive / Q000503:physiopathology*; D014554:Urination / Q000502:physiology; D014563:Urodynamics; D019459:Urothelium / Q000503:physiopathology*
chemical_list: D019012:Integrin beta1
references: Am J Physiol Renal Physiol. 2004 Aug;287(2):F305-18
references: 15068973
references: Cell Adhes Commun. 1995 Aug;3(3):231-42
references: 8846024
references: Mol Biol Cell. 2009 Jan;20(1):282-95
references: 18987341
references: Am J Physiol Renal Physiol. 2011 Jan;300(1):F49-59
references: 20943764
references: Auton Neurosci. 2010 Feb 16;153(1-2):33-40
references: 19666243
references: BMC Dev Biol. 2001;1:4
references: 11299042
references: Am J Pathol. 1994 May;144(5):1016-22
references: 8178925
references: Am J Physiol Renal Physiol. 2006 Aug;291(2):F332-40
references: 16597611
references: J Cell Biol. 2005 Nov 21;171(4):717-28
references: 16301336
references: J Clin Invest. 2007 Nov;117(11):3453-62
references: 17948126
references: J Cell Biol. 2000 Sep 4;150(5):1149-60
references: 10974002
references: EMBO J. 2010 Jun 16;29(12):1961-75
references: 20461056
references: J Cell Sci. 2009 Jan 15;122(Pt 2):179-86
references: 19118210
references: J Physiol. 1997 Dec 1;505 ( Pt 2):503-11
references: 9423189
references: PLoS One. 2011 Apr 14;6(4):e18704
references: 21533188
references: Urology. 2004 Dec;64(6 Suppl 1):7-11
references: 15621221
references: J Physiol. 2005 Sep 1;567(Pt 2):621-39
references: 15961431
references: Kidney Int. 2007 Nov;72(9):1057-64
references: 17667988
references: J Biol Chem. 2011 Jun 10;286(23):20778-87
references: 21388952
references: J Biol Chem. 2004 Mar 26;279(13):12001-4
references: 14960578
references: J Cell Biol. 2006 Nov 6;175(3):505-14
references: 17088430
references: J Urol. 2000 Jun;163(6):2002-7
references: 10799247
references: Am J Physiol Renal Physiol. 2008 Apr;294(4):F919-27
references: 18256316
references: Handb Exp Pharmacol. 2009;(194):91-138
references: 19655106
references: J Neurosci. 2001 Aug 1;21(15):5670-7
references: 11466438
references: Int Rev Cell Mol Biol. 2010;279:135-90
references: 20797679
references: Nat Neurosci. 2002 Sep;5(9):856-60
references: 12161756
references: Nature. 2000 Oct 26;407(6807):1011-5
references: 11069181
references: Pharmacology. 2001;63(2):120-8
references: 11490205
references: Am J Physiol Renal Physiol. 2003 Oct;285(4):F651-63
references: 12770841
references: Trends Cell Biol. 2006 Dec;16(12):631-9
references: 17064899
references: Dev Biol. 2008 Jan 15;313(2):584-93
references: 18082680
references: Am J Pathol. 1994 Nov;145(5):1199-207
references: 7977650
references: World J Urol. 1996;14 Suppl 1:S30-7
references: 8738408
references: Dev Biol. 2007 Jun 15;306(2):658-68
references: 17493607
references: Am J Physiol Renal Physiol. 2003 May;284(5):F966-76
references: 12527557
references: Sci STKE. 2002 Feb 12;2002(119):pe6
references: 11842240
references: Mol Biol Cell. 2002 Mar;13(3):830-46
references: 11907265
references: J Biol Chem. 2005 Apr 29;280(17):16546-9
references: 15760908
references: Am J Physiol Renal Physiol. 2002 Aug;283(2):F242-53
references: 12110507
references: Am J Physiol. 1996 Oct;271(4 Pt 2):F886-94
references: 8898019
references: Am J Pathol. 1994 Apr;144(4):787-95
references: 7512792
references: Kidney Int. 2009 Jun;75(11):1153-1165
references: 19340092