Glomerulogenesis and renal tubular differentiation : role of HNF1β

Abstract : Hepatocyte Nuclear factor 1 beta (HNF1beta) is a transcription factor expressed in epithelial cells of different organs, such as pancreas, intestine and kidney. The most penetrant phenotypic trait in patients carrying HNF1B mutations is the presence of renal abnormalities, frequently associated with Maturity Onset Diabetes of the Young type 5 (MODY5). During my thesis, I analyzed the role played by this transcription factor in different compartments and at different time points in mouse kidney, using a Cre LoxP strategy. Our laboratory has previously shown that Hnf1b specific inactivation in the epithelial nephron precursors cells (Six2Cre) leads to defective tubular specification and expansion and to the formation of glomerular cysts. The analysis of the morphogenetic processes of glomerulogenesis in the absence of HNF1beta led me to propose a new mechanism of glomerular cyst formation. In mutant nephron, the connection between the glomerulus and the tubular component is abnormally trapped inside the glomerular cup. Due to this unusual configuration, the trapped tubule is surrounded by capillaries and mesangial cells, leading to a constriction of the urinary glomerular outflow. When filtration starts, the production of the primary urine might induce the dilation of the Bowman capsule and the formation of glomerular cyst. In the second part of my thesis, I analyzed the role played by Hnf1b in proliferative versus quiescent tubular cells, by inactivating this gene in renal tubules at different time points (inducible Ksp-CreERT2). My results showed that Hnf1b inactivation during postnatal tubular elongation leads to polycystic kidney disease, as previously described in our laboratory. Analysis of this new inducible model of Hnf1b inactivation also highlighted for the first time a fibrotic phenotype in the tissue surrounding the cysts. The later inactivation in a more quiescent status is characterized by the presence of focal tubulointerstitial fibrosis and tubular dilation. Interestingly, in this context, Hnf1b-deficient proximal tubular cells present a partial loss of epithelial differentiation, characterized by a reduced expression of tubular markers (LTL) and de novo expression of vimentin. At the molecular level, the expression of Zeb2, a transcription factor involved in epithelial to mesenchymal transition, is increased. This is due to the downregulation of its inhibitor miR200, a direct target of HNF1beta. Finally, transcriptomical analyses in postnatal and postweaning periods showed that two major pathways are commonly affected. The development and differentiation of nephrons are severely compromised and pro-inflammatory and fibrotic signaling cascades are strongly upregulated. All together these results improved our knowledge about the role of HNF1beta in glomerulogenesis and adult kidney.
Keywords : Development
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Arianna Fiorentino. Glomerulogenesis and renal tubular differentiation : role of HNF1β. Human health and pathology. Université Sorbonne Paris Cité, 2016. English. ⟨NNT : 2016USPCB121⟩. ⟨tel-02180581⟩

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