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Published on: October 12, 2017
Transcriptional dysregulation in the ureteric bud causes multicystic dysplastic kidney by branching morphogenesis
Qiusha Guo1, Piyush Tripathi2, Scott R Manson3
1Washington University School of Medicine, St. Louis, Missouri.
Purpose:
The calcineurin-NFAT signaling pathway regulates the transcription of genes important for development. It is impacted by various genetic and environmental factors. We investigated the potential role of NFAT induced transcriptional dysregulation in the pathogenesis of congenital abnormalities of the kidneys and urinary tract.
Materials And Methods:
A murine model of conditional NFATc1 activation in the ureteric bud was generated and examined for histopathological changes. Metanephroi were also cultured in vitro to analyze branching morphogenesis in real time.
Results:
NFATc1 activation led to defects resembling multicystic dysplastic kidney. These mutants showed severe disorganization of branching morphogenesis characterized by decreased ureteric bud branching and the disconnection of ureteric bud derivatives from the main collecting system. The orphan ureteric bud derivatives may have continued to induce nephrogenesis and likely contributed to the subsequent formation of blunt ended filtration units and cysts. The ureter also showed irregularities consistent with impaired epithelial-mesenchymal interaction.
Conclusions:
This study reveals the profound effects of NFAT signaling dysregulation on the ureteric bud and provides insight into the pathogenesis of multicystic dysplastic kidney. Our results suggest that the obstruction hypothesis and the bud theory may not be mutually exclusive to explain the pathogenesis of multicystic dysplastic kidney. Ureteric bud dysfunction such as that induced by NFAT activation can disrupt ureteric bud-metanephric mesenchyma interaction, causing primary defects in branching morphogenesis, subsequent dysplasia and cyst formation. Obstruction of the main collecting system can further enhance these defects, producing the pathological changes associated with multicystic dysplastic kidney.
Insights
NFAT signaling dysregulation in the ureteric bud causes kidney abnormalities. This study reveals how NFAT activation leads to ureteric bud dysfunction and multicystic dysplastic kidney development.
Area of Science:
- Developmental Biology
- Molecular Biology
- Genetics
Background:
- The calcineurin-NFAT signaling pathway is crucial for gene transcription during development.
- This pathway is influenced by genetic and environmental factors.
- Dysregulation of NFAT-mediated transcription may contribute to congenital abnormalities.
Purpose of the Study:
- To investigate the role of NFAT-induced transcriptional dysregulation in the pathogenesis of congenital abnormalities of the kidneys and urinary tract (CAKUT).
- To understand the impact of NFAT signaling on ureteric bud development and kidney formation.
Main Methods:
- Generated a murine model with conditional NFATc1 activation in the ureteric bud.
- Examined histopathological changes in the murine model.
- Utilized in vitro organ culture of metanephroi to analyze real-time branching morphogenesis.
Main Results:
- NFATc1 activation induced defects resembling multicystic dysplastic kidney (MCDK).
- Observed severe disorganization of branching morphogenesis, decreased ureteric bud branching, and disconnection of ureteric bud derivatives.
- Noted formation of cysts and blunt-ended filtration units, along with impaired epithelial-mesenchymal interactions in the ureter.
Conclusions:
- NFAT signaling dysregulation profoundly affects the ureteric bud, offering insights into MCDK pathogenesis.
- Ureteric bud dysfunction due to NFAT activation disrupts ureteric bud-metanephric mesenchyme interaction, leading to dysplasia and cyst formation.
- Obstruction may exacerbate these defects, contributing to MCDK pathology; obstruction and bud theories may coexist.
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