Kidney epithelial cells operate under high mechanical stress and require biochemical responses to maintain proper morphology and function. This study investigates how the mechanosensitive channel Piezo contributes to mechanotransduction in Drosophila melanogaster nephrocytes. This work shows that Piezo regulates intracellular Ca++ levels in response to shear stress, which leads to increased Rho1 GTPase activity and downstream actin remodeling. Piezo overexpression impairs the acute response to shear stress, a phenotype that is rescued by the inhibition of mechanosensitive channels. The authors describe a new mechanical signaling pathway that drives cytoskeletal remodeling in response to shear stress in the fly renal system. They link their findings to human gene expression data from patient populations showing that Piezo2 is up-regulated in multiple disease states, connecting the molecular signaling to physiological outcomes. This preprint has been assigned the following badges: Cross-Validation, New Hypothesis. Read the preprint on bioRxiv ( Koehler et al., 2022 ): https://doi.org/10.1101/2021.10.23.465463 .