Effects of transforming growth factor on the developing embryonic ureter: An in-vitro megaureter model in mice.
BACKGROUND
It is generally agreed that the cause of a megaureter is narrowing at the vesicoureteral junction, with a functional obstruction arising from an aperistaltic, juxtavesical segment that is unable to transport urine at an acceptable rate. Histological examinations of megaureter specimens have reported several histological analyses, and the pathogenic role of transforming growth factor is still a matter of speculation.


OBJECTIVE
To evaluate whether transforming growth factor-beta (TGF-β) and its receptors (TGFRs) are expressed during ureterovesical junction (UVJ) and lower ureter development in mice, and whether exogenous TGF-β might postpone the maturation of smooth muscle cells, in the pathogenesis of megaureter using an embryonic organ-culture model.


METHODS
Expression of TGF-β and TGFRs on the lower ureter and UVJ were determined at different embryonic days (E) (E16, 18, 20 and postnatal day 1). The functional studies were performed by harvesting ureters from wild-type mice at embryonic day 16 (E16), which were grown in serum-free organ-culture; some cultures were supplemented with TGF-β (2 and 20 ng/ml) and/or with soluble TGFR, which blocks bioactivity. Organs were harvested after 6 days and the expression of CD31 and Ki67 were assessed using immunohistochemistry. The muscle content of the UVJ and ureter were analyzed by flowcytometry.


RESULTS
The TGF-β and TGFR positive cells were immune detected in embryonic ureters. The TGF-β expression was highest on E18 and decreased postnatally. Exogenous TGF-β decreased ureterovesical (UV) muscle differentiation and proliferation. The longitudinal muscle fibers were significantly less in TGF-β explants. The TGF-β also decreased the proportions of cells expressing α smooth muscle actin (α-SMA). Soluble TGFR blocked the effects of exogenous TGF-β.


CONCLUSIONS
In organ culture, exogenous TGF-β postpones the UV smooth muscle proliferation and affects the muscular structure. Whether the effects of TGF-β are direct or indirect, these form an in-vitro megaureter model. The finding that TGF-β is highest in embryonic ureters in vivo and decreased postnatally suggests that a pathological persistence might potentially explain the pathogenesis of primary megaureters.
Department of Urology, School of Medicine, Ankara University, Ankara, Turkey. Electronic address: ozturkerdem583@gmail.com.
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Ozturk
Department of Pediatric Urology, School of Medicine, Ankara University, Ankara, Turkey.
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Telli
Department of Urology, School of Medicine, Ankara University, Ankara, Turkey.
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Gokce
Department of Urology, School of Medicine, Ankara University, Ankara, Turkey.
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Ozcan
Department of Urology, School of Medicine, Ankara University, Ankara, Turkey.
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Okutucu
Department of Pediatric Urology, School of Medicine, Ankara University, Ankara, Turkey.
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Soygur
Department of Pediatric Urology, School of Medicine, Ankara University, Ankara, Turkey.
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Burgu
D000818:Animals; D004108:Dilatation, Pathologic / Q000196:embryology; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D051379:Mice; D018125:Receptors, Transforming Growth Factor beta / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology*; D014513:Ureter / Q000196:embryology* / Q000473:pathology; D014515:Ureteral Diseases / Q000196:embryology*
D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta
Embryo; Megaureter; Mice; Transforming growth factor