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Contrôle post-transcriptionnel de l'expression rénale du récepteur minéralocorticoide par les variations de tonicité extracellulaire : conséquences physiopathologiques.

Abstract : Aldosterone and the Mineralocorticoid Receptor (MR) participate to the control of salt and water balance and the arterial pressure. Alteration of renal MR expression or mineralocorticoid signaling pathway contributes to the development of numerous human disorders. In this work, we have demonstrated the major role played by the RNA-Binding Proteins, Tis11b and HuR, in the control of MR expression in response to variations of extracellular tonicity in a model of principal tubular cells and in vivo. Hypertonicity (500 mOsmol/L) increases the expression ofTis11b, which binds the 3’-untranslated region of MR transcript and accelerates the degradation of MR transcript, leading to the reduction of the mineralocorticoid signaling. Conversely, hypotonicity (150 mOsmol/L) stimulates nuclear-cytoplasmic shuttling of HuR protein, which stabilizes MR transcript increasing its expression and renal sensitivity to aldosterone action. Furthermore, HuR participates to the editing of the novel MR Δ6 splice variant, which lacks exon 6, and exerts a dominant negative effect on mineralocorticoid signaling. Finally, we have provided evidence that hypertonicity modulates expression of microRNA, which may control mineralocorticoid signaling pathway. Characterization of these original mechanisms modulating MR action is pivotal for a better understanding of mineralocorticoid-related pathophysiology, and should ultimately lead to the development of new therapeutic strategies.
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  • HAL Id : tel-03381206, version 1

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Ingrid Lema. Contrôle post-transcriptionnel de l'expression rénale du récepteur minéralocorticoide par les variations de tonicité extracellulaire : conséquences physiopathologiques.. Biologie moléculaire. Université Paris Saclay (COmUE), 2016. Français. ⟨NNT : 2016SACLS290⟩. ⟨tel-03381206⟩

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