Antagonism of BMP4 Signaling Disrupts Smooth Muscle Investment of the Ureter and Ureteropelvic Junction

No AccessJournal of UrologyInvestigative Urology1 Jan 2009Antagonism of BMP4 Signaling Disrupts Smooth Muscle Investment of the Ureter and Ureteropelvic Junction Gerald J. Wang, Andrea Brenner-Anantharam, E. Darracott Vaughan, and Doris Herzlinger Gerald J. WangGerald J. Wang More articles by this author , Andrea Brenner-AnantharamAndrea Brenner-Anantharam More articles by this author , E. Darracott VaughanE. Darracott Vaughan More articles by this author , and Doris HerzlingerDoris Herzlinger More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2008.08.117AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: Congenital ureteropelvic junction obstruction has been associated with aberrant ureteral smooth muscle organization. Recent evidence has shown that BMP4 may be involved in ureteral morphogenesis. We determined whether the disruption of BMP4 signaling results in abnormal smooth muscle investment of the ureter and ureteropelvic junction. Materials and Methods: We used a Cre mediated Bmp4 knockout system to conditionally excise the Bmp4 gene in developing mouse embryos. Kidney rudiments were isolated from embryos at varying gestational ages from WT and conditional knockout mice. Metanephric kidney explants were cultured in the presence or absence of the BMP antagonist Noggin. Agarose beads pre-incubated with Gremlin, another BMP antagonist, were used for localized disruption of BMP signaling. Frozen sections and whole metanephric explants were then analyzed by immunofluorescence. Results: Bmp4 gene excision resulted in a dose dependent loss of ureteral smooth muscle. Antagonism of BMP signaling inhibited ureteral smooth muscle investment in a dose dependent manner and was paralleled by a dose dependent decrease in the immediate downstream targets of BMP signaling, phosphorylated Smad1, 5 and 8. Localized antagonism of BMP resulted in the focal disruption of ureteral smooth muscle investment. Conclusions: We report that decreased BMP signaling, whether by the loss of BMP4 in vivo or direct antagonism in vitro, results in a gradual reduction of the normal, well organized coat of smooth muscle surrounding the ureter. Our results also suggest that this occurs via a direct Smad dependent pathway. This raises the possibility that abnormalities in BMP4 signaling may have a role in the development of congenital ureteropelvic junction obstruction. References 1 : Abnormal innervation and altered nerve growth factor messenger ribonucleic acid expression in ureteropelvic junction obstruction. J Urol1995; 154: 679. 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Google Scholar Departments of Urology and Physiology and Biophysics (ABA, DL), New York-Presbyterian Hospital, Weill Medical College of Cornell University, New York, New York© 2009 by American Urological AssociationFiguresReferencesRelatedDetails Volume 181Issue 1January 2009Page: 401-407 Advertisement Copyright & Permissions© 2009 by American Urological AssociationKeywordsgene expressionureteral obstructionabnormalitiesureterbone morphogenetic protein 4AcknowledgmentsBrigid Hogan, Duke University, Durham, North Carolina provided mice homozygous for the Bmp4 conditional allele.MetricsAuthor Information Gerald J. Wang More articles by this author Andrea Brenner-Anantharam More articles by this author E. Darracott Vaughan More articles by this author Doris Herzlinger More articles by this author Expand All Advertisement PDF downloadLoading ...