Effects of transforming growth factor on the developing embryonic ureter: An in-vitro megaureter model in mice

Öztürk, Erhan Arif; Telli, Onur; Gökçe, Mehmet İlker; Özcan, Cihat; Okutucu, Tolga Muharrem; Soygür, Tarkan; Burgu, Berk

doi:10.1016/j.jpurol.2016.04.039

Cited by 4 publications

(4 citation statements)

References 19 publications

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“…This hypothesis is supported by the findings of Ozturk and colleagues, who described that TGFβ is highest in embryonic ureters in vivo and decreases postnatally. 19 Positive TGFβ immunoreactions were detected in the ureter from 6-to 12-month-old patients with obstructed primary megaureter. Such reactions weakened progressively in those patients older than 1 year, becoming negative in all children older than 3 years.…”

Section: Discussionmentioning

confidence: 93%

“…[16][17][18] In organ culture, exogenous TGFβ postpones the ureterovesical smooth muscle proliferation and affects the muscular structure. 19 Fibroblast growth factor (FGF) is a group of growth factors that plays role in a kidney and lower urinary tract development, for instance, nephron progenitor differentiation in nephrons and development of ureteric epithelium. 20 Fibroblast growth factor receptor 1 (FGFR1) is an FGF receptor with tyrosine kinase activity.…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of PGP 9.5, NGFR, TGFβ1, FGFR1, MMP-2, AT2R2, SHH, and TUNEL in Primary Obstructive Megaureter Tissue

Junga

Siņicins

Pētersons

et al. 2021

J Histochem Cytochem.

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Primary obstructive megaureter (POM) morphogenesis is not fully known. The aim of the study was to evaluate the appearance of different factors that might take part in the pathogenesis of POM. Megaureter tissues of 14 children were stained with hematoxylin and eosin as well as with immunohistochemistry for protein gene product 9.5, nerve growth factor receptor, transforming growth factor beta 1 (TGFβ1), fibroblast growth factor receptor 1 (FGFR1), matrix metalloproteinase 2 (MMP-2), angiotensin 2 receptor type 2, and sonic hedgehog (SHH) protein. Apoptosis was detected by terminal dUTP nick-end labeling reaction. POM tissues revealed transitional epithelium with scattered vacuolization, submucosa with inflammatory cells, and focally vacuolized and chaotically organized muscle layers. Apoptosis, appearance of MMP-2, FGFR1, and SHH prevailed, but TGFβ1 positive cell number was lower in patients. Correlation between MMP-2 in epithelium and endothelium, FGFR1 and MMP-2 in epithelium, and TGFβ1 in epithelium and connective tissue in patients was detected. POM morphopathogenesis involves an apoptotic cell death of epithelium and smooth muscle as well as tissue degradation in epithelium and connective tissue of the ureter wall. The decrease of tissue growth through diminished TGFβ1 expression and stimulation of FGFR1 and MMP-2 suggests a disbalance of tissue remodelation in the megaureter wall:

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Evaluation of PGP 9.5, NGFR, TGFβ1, FGFR1, MMP-2, AT2R2, SHH, and TUNEL in Primary Obstructive Megaureter Tissue

Junga

Siņicins

Pētersons

et al. 2021

J Histochem Cytochem.

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show abstract

“…On the other hand, exogenous TGFβ1 is reported to decrease proliferation of postnatal urothelia and ureteric bud tips , and it compromises branching morphogenesis in salivary glands and lung . Another study reported that embryonic rat ureters exposed to TGFβ had impaired urothelial and SM proliferation . That study , however, neither showed images of growing organs nor assessed gene expression.…”

Section: Discussionmentioning

confidence: 95%

“…Another study reported that embryonic rat ureters exposed to TGFβ had impaired urothelial and SM proliferation . That study , however, neither showed images of growing organs nor assessed gene expression.…”

Section: Discussionmentioning

confidence: 96%

Overactivity or blockade of transforming growth factor‐β each generate a specific ureter malformation

Lopes

Roberts

Zeef

et al. 2019

The Journal of Pathology

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Transforming growth factor- (TGF) has been reported to be dysregulated in malformed ureters. There exists, however, little information on whether altered TGF levels actually perturb ureter development. We therefore hypothesised that TGF has functional effects on ureter morphogenesis. Tgfb1, Tgfb2 and Tgfb3 transcripts coding for TGF ligands, as well as Tgfbr1 and Tgfbr2 coding for TGF receptors, were detected by quantitative polymerase chain reaction in embryonic mouse ureters collected over a wide range of stages. As assessed by in situ hybridisation and immunohistochemistry, the two receptors were detected in embryonic urothelia. Next, TGF1 was added to serum-free cultures of embryonic day 15 mouse ureters. These organs contain immature smooth muscle and urothelial layers and their in vivo potential to grow and acquire peristaltic function can be replicated in serum-free organ culture. Such organs therefore constitute a suitable developmental stage with which to define roles of factors that affect ureter growth and functional differentiation. Exogenous TGF1 inhibited growth of the ureter tube and generated cocoon-like dysmorphogenesis. RNA sequencing suggested that altered levels of transcripts encoding certain fibroblast growth factors (FGFs) followed exposure to TGF. In serum-free organ culture exogenous FGF10 but not FGF18 abrogated certain dysmorphic effects mediated by exogenous TGF1. To assess whether an endogenous TGF axis functions in developing ureters, embryonic day 15 explants were exposed to TGF receptor chemical blockade; growth of the ureter was enhanced, and aberrant bud-like structures arose from the urothelial tube. The muscle layer was attenuated around these buds, and peristalsis was compromised. To determine whether TGF effects were limited to one stage, explants of mouse embryonic day 13 ureters, more primitive organs, were exposed to exogenous TGF1, again generating cocoon-like structures, and to TGF receptor blockade, again generating ectopic buds. As for the mouse studies, immunostaining of normal embryonic human ureters detected TGFRI and TGFRII in urothelia. Collectively, these observations reveal unsuspected regulatory roles for endogenous TGF in embryonic ureters, fine-tuning morphogenesis and functional differentiation. Our results also support the hypothesis that the TGF up-regulation reported in ureter malformations impacts on pathobiology. Further experiments are needed to unravel the intracellular signalling mechanisms involved in these dysmorphic responses.

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The etiology of congenital obstructive uropathy: developmental and genetic perspectives

ten Hoor,

Becknell,

Hohenstein

et al. 2024

Current Topics in Developmental Biology

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Effects of transforming growth factor on the developing embryonic ureter: An in-vitro megaureter model in mice

Cited by 4 publications

References 19 publications

Evaluation of PGP 9.5, NGFR, TGFβ1, FGFR1, MMP-2, AT2R2, SHH, and TUNEL in Primary Obstructive Megaureter Tissue

Evaluation of PGP 9.5, NGFR, TGFβ1, FGFR1, MMP-2, AT2R2, SHH, and TUNEL in Primary Obstructive Megaureter Tissue

Overactivity or blockade of transforming growth factor‐β each generate a specific ureter malformation

The etiology of congenital obstructive uropathy: developmental and genetic perspectives

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