The AMPK-Sirtuin 1-YAP axis is regulated by fluid flow intensity and controls autophagy flux in kidney epithelial cells

Aurore Claude-Taupin (), Pierre Isnard, Alessia Bagattin, Nicolas Kuperwasser, Federica Roccio, Biagina Ruscica, Nicolas Goudin, Meriem Garfa-Traoré, Alice Regnier, Lisa Turinsky, Martine Burtin, Marc Foretz, Marco Pontoglio, Etienne Morel, Benoit Viollet, Fabiola Terzi, Patrice Codogno and Nicolas Dupont ()
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Aurore Claude-Taupin: Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants Malades
Pierre Isnard: Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants Malades
Alessia Bagattin: Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants Malades
Nicolas Kuperwasser: Structure Fédérative de Recherche Necker
Federica Roccio: Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants Malades
Biagina Ruscica: Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants Malades
Nicolas Goudin: Structure Fédérative de Recherche Necker
Meriem Garfa-Traoré: Structure Fédérative de Recherche Necker
Alice Regnier: Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants Malades
Lisa Turinsky: Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants Malades
Martine Burtin: Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants Malades
Marc Foretz: Inserm U1016 - CNRS UMR8104 – Université Paris Cité
Marco Pontoglio: Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants Malades
Etienne Morel: Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants Malades
Benoit Viollet: Inserm U1016 - CNRS UMR8104 – Université Paris Cité
Fabiola Terzi: Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants Malades
Patrice Codogno: Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants Malades
Nicolas Dupont: Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants Malades

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract Shear stress generated by urinary fluid flow is an important regulator of renal function. Its dysregulation is observed in various chronic and acute kidney diseases. Previously, we demonstrated that primary cilium-dependent autophagy allows kidney epithelial cells to adapt their metabolism in response to fluid flow. Here, we show that nuclear YAP/TAZ negatively regulates autophagy flux in kidney epithelial cells subjected to fluid flow. This crosstalk is supported by a primary cilium-dependent activation of AMPK and SIRT1, independently of the Hippo pathway. We confirm the relevance of the YAP/TAZ-autophagy molecular dialog in vivo using a zebrafish model of kidney development and a unilateral ureteral obstruction mouse model. In addition, an in vitro assay simulating pathological accelerated flow observed at early stages of chronic kidney disease (CKD) activates YAP, leading to a primary cilium-dependent inhibition of autophagic flux. We confirm this YAP/autophagy relationship in renal biopsies from patients suffering from diabetic kidney disease (DKD), the leading cause of CKD. Our findings demonstrate the importance of YAP/TAZ and autophagy in the translation of fluid flow into cellular and physiological responses. Dysregulation of this pathway is associated with the early onset of CKD.

Date: 2023
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DOI: 10.1038/s41467-023-43775-1

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