title: Urinary Retention, Incontinence, and Dysregulation of Muscarinic Receptors in Male Mice Lacking Mras.
abstract: Here we show that male, but not female mice lacking expression of the GTPase M-Ras developed urinary retention with distention of the bladder that exacerbated with age but occurred in the absence of obvious anatomical outlet obstruction. There were changes in detrusor morphology in Mras-/- males: Smooth muscle tissue, which exhibited a compact organization in WT mice, appeared disorganized and became increasingly 'layered' with age in Mras-/- males, but was not fibrotic. Bladder tissue near the apex of bladders of Mras-/- males exhibited hypercontractility in response to the cholinergic agonist carbachol in in vitro, while responses in Mras-/- females were normal. In addition, spontaneous phasic contractions of detrusors from Mras-/- males were increased, and Mras-/- males exhibited urinary incontinence. We found that expression of the muscarinic M2 and M3 receptors that mediate the cholinergic contractile stimuli of the detrusor muscle was dysregulated in both Mras-/- males and females, although only males exhibited a urinary phenotype. Elevated expression of M2R in young males lacking M-Ras and failure to upregulate M3R with age resulted in significantly lower ratios of M3R/M2R expression that correlated with the bladder abnormalities. Our data suggests that M-Ras and M3R are functionally linked and that M-Ras is an important regulator of male bladder control in mice. Our observations also support the notion that bladder control is sexually dimorphic and is regulated through mechanisms that are largely independent of acetylcholine signaling in female mice.
authors.affiliation: The Biomedical Research Centre, The University of British Columbia, 2222 Health Sciences Mall, Vancouver, British Columbia, Canada.
authors.forename: Annette
authors.initials: A
authors.lastname: Ehrhardt
authors.affiliation: The Biomedical Research Centre, The University of British Columbia, 2222 Health Sciences Mall, Vancouver, British Columbia, Canada.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.affiliation: The University of British Columbia MRI Research Centre, Life Sciences Centre, 2350 Health Sciences Mall, Vancouver, British Columbia, Canada.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Yung
authors.affiliation: The Biomedical Research Centre, The University of British Columbia, 2222 Health Sciences Mall, Vancouver, British Columbia, Canada.
authors.forename: Yanni
authors.initials: Y
authors.lastname: Wang
authors.affiliation: The University of British Columbia MRI Research Centre, Life Sciences Centre, 2350 Health Sciences Mall, Vancouver, British Columbia, Canada; The University of British Columbia, Departments of Radiology and Urologic Sciences, 818 West 10th Ave., Vancouver, British Columbia, Canada.
authors.forename: Piotr
authors.initials: P
authors.lastname: Kozlowski
authors.affiliation: The University of British Columbia, Department of Pharmacology and Therapeutics, 2176 Health Sciences Mall, Vancouver, British Columbia, Canada.
authors.forename: Cornelis
authors.initials: C
authors.lastname: van Breemen
authors.affiliation: The Biomedical Research Centre, The University of British Columbia, 2222 Health Sciences Mall, Vancouver, British Columbia, Canada.
authors.forename: John W
authors.initials: JW
authors.lastname: Schrader
mesh_terms: D000109:Acetylcholine / Q000502:physiology; D000375:Aging / Q000235:genetics / Q000502:physiology; D000818:Animals; D005260:Female; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020559:Monomeric GTP-Binding Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000378:metabolism; D010641:Phenotype; D011507:Proteinuria / Q000235:genetics / Q000503:physiopathology; D012333:RNA, Messenger / Q000096:biosynthesis; D043585:Receptor, Muscarinic M2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D043587:Receptor, Muscarinic M3 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D012727:Sex Characteristics; D001743:Urinary Bladder / Q000378:metabolism* / Q000473:pathology; D053201:Urinary Bladder, Overactive / Q000235:genetics / Q000503:physiopathology; D014549:Urinary Incontinence / Q000235:genetics / Q000503:physiopathology*; D016055:Urinary Retention / Q000235:genetics / Q000503:physiopathology*; D014554:Urination / Q000502:physiology; D018631:ras Proteins
chemical_list: D012333:RNA, Messenger; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; C109418:Mras protein, mouse; D020559:Monomeric GTP-Binding Proteins; D018631:ras Proteins; D000109:Acetylcholine