Podocytes are important structural and functional roles in maintaining the filtration barrier specialized epithelial cells in the kidney glomerulus. Translational Researchers have revealed that results of Nephrotic syndrome, breakdown of the kidney filtration barrier and is associated with proteinuria, hyperlipidemia, and edema. Moreover, podocytes change in morphology and internalize plasma proteins in response to this disorder. Here, we used fluid-phase tracers in murine models and determined that podocytes actively internalize fluid from the plasma and that the rate of internalization is increased when the filtration barrier is disrupted. Refined podocytes for the presence of free fatty acids associated with serum albumin stimulated macropinocytosis through a pathway that involves free fatty acids receptors, the Gβ/Gγ complex and RAC1. Moreover, mice with elevated levels of plasma free fatty acids as the result of a high-fat diet were more susceptible to Adriamycin-induced proteinuria than were animals on standard chow. Together, these results support a model in which podocytes sense the disruption of the filtration barrier via free fatty acids bound to albumin and respond by enhancing fluid-phase uptake. The response to free fatty acids may function in the development of nephrotic syndrome by amplifying the effects of proteinuria.