SPLASH

Shear stress generated by physiological urinary fluid flow is an important regulator of renal function. However, abnormal shear stress (pathological flow) is observed in chronic kidney diseases (CKD), affecting close to 3 million people in France. Despite recent progress in our understanding of flow-regulated processes in renal cells, the precise cellular and molecular pathways required to protect them from the stress induced by physiological and pathological urinary flow are currently unknown. The plasma membrane functions as the first physical sensor of shear stress, and urinary flow helps maintain plasma membrane integrity in kidney tubular cells. However, shear stress can also induce physical breaches to the plasma membrane and remodel its lipid composition, thus affecting plasma membrane tension and turnover. Moreover, the primary cilium, a specialized plasma membrane protrusion, is an important asset for kidney cells to sense urinary fluid flow variations. Indeed, in physiological conditions, the primary cilium supports the metabolic adaptation of renal cells through autophagy activation. However, we recently discovered that mimicking CKD in vitro (increasing flow intensity simulating CKD) inhibited the primary cilium-dependent activation of autophagy. We hypothesized that amplifying physical injuries on the apical surface of kidney epithelial cells could disturb renal cell homeostasis. The aim of the SPLASH project is to investigate how physiological and pathological flow affect plasma membrane and primary cilium integrity in kidney epithelial cells, to better understand the early events driving CKD progression. We will also study the mechanisms regulating plasma membrane and primary cilium homeostasis, which could lead to the release of components and vesicles into the extracellular medium, carrying specific signals to distal parts of the nephron and potentially contributing to CKD progression. We believe that characterizing the secretory signature of renal cells submitted to physiological and pathological flow will help us identify novel biomarker candidates for early CKD detection. Hence, the SPLASH project, by enhancing our understanding of the mechanisms governing the maintenance of plasma membrane and primary cilium homeostasis, will propose new avenues for CKD diagnosis and delineate their implications in CKD progression.