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The AMPK-Sirtuin 1-YAP axis is regulated by fluid flow intensity and controls autophagy flux in kidney epithelial cells
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Edité par CCSD ; Nature Publishing Group -
International audience. 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.The development and function of organs is tightly controlled by mechanical forces 1,2 . In the kidney, mechanical forces, such as shear stress induced by urinary fluid flow, are the principal regulators of proximal reabsorption. Indeed, forces regulate active transport mechanisms in the proximal tubule to drive the reabsorption of up to 70% of Na + , K + , H + , NH 4 + , Cl -, HCO 3 -, Ca 2+ , inorganic phosphate, lowmolecular-weight proteins, glucose and water from the glomerular ultrafiltrate into the blood 3 . Altered tissue mechanics are now recognized to have an active role in driving human diseases 4-7 . However, how mechanical alterations participate in the early stages of renal diseases, such as chronic kidney disease (CKD), is still unclear.In kidney proximal tubules, the primary cilium, a microtubulebased organelle present at the apical surface of epithelial cells, acts as a flow sensor to integrate variations in flow rates of the glomerular ultrafiltrate. We and others have demonstrated an interplay between macroautophagy (hereafter referred to as autophagy) and primary cilia 8-10 . Recently, we showed that primary cilium-dependent autophagy is activated through an LKB1-AMPK signaling pathway to regulate.
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