Abstract 10915: Unappreciated Mechanisms of Fatty Acid Uptake in the Kidney: Fatty Acids Are Taken Up from Both Basolateral and Apical Side

Abstract

Introduction: The kidney combusts a large amount of fatty acid (FA) for body fluid homeostasis. Despite the high demand for FA, however, little is known about the mechanisms of FA uptake. We aimed to determine how FAs are taken up by tubular epithelial cells. Methods and Results: Immunohistochemistry showed that CD36, known as an important FA transporter in the heart, was also expressed in the basolateral side of proximal tubule epithelial cells (PTECs). The uptake of 125 I-BMIPP, radio-labeled FA tracer, was significantly reduced in the kidney in CD36 knockout mice 1 min after its injection compared with wild-type mice, while the significant difference disappeared 30 min after the injection. In vivo imaging with two-photon microscopy revealed that BODIPY-C 12 , fluorescence-labeled FA tracer, was accumulated in the basolateral side (blood side) of PTECs shortly after its injection, which was followed by accumulation in the apical side (primary urine side), suggesting bidirectional FA uptake by PTECs. A large amount of neutral lipid was accumulated in the kidney when serum FA concentration was increased by accelerated lipolysis by administration of a β3 adrenergic receptor agonist. Immunofluorescence with cell-specific antibodies revealed that the cells with the most abundant lipid accumulation were PTECs, followed by tubular epithelial cells of the distal nephron. In addition, neutral lipid accumulation was enhanced even in the distal nephron when PTECs were injured with administrations of diphtheria toxin (DT) in mice overexpressing DT-receptor in a PTEC-specific manner. Importantly, the PTEC-injured mice exhibited marked albuminuria, suggesting disturbance of protein reabsorption. Despite marked albuminuria, however, urinary FA was not detected at all, suggesting complete FA reabsorption independently of albumin reabsorption in the kidney. Conclusions: Our results revealed the unique and prominent capability of proximal and distal tubular epithelial cells to take up FA from both blood (CD36-dependent) and primary urine (CD36-independent) and to store them as neutral lipids. We further suggest that the kidney acts not only as FA consuming tissue but also as FA keeping tissue to completely reabsorb FA from primary urine for unwasted energy use.