Albumin-associated free fatty acids induce macropinocytosis in podocytes
Jun-Jae Chung, … , Jeffrey H. Miner, Andrey S. Shaw
Jun-Jae Chung, … , Jeffrey H. Miner, Andrey S. Shaw
Published April 27, 2015
Citation Information: J Clin Invest. 2015;125(6):2307-2316. https://doi.org/10.1172/JCI79641.
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Research Article Nephrology

Albumin-associated free fatty acids induce macropinocytosis in podocytes

Abstract

Podocytes are specialized epithelial cells in the kidney glomerulus that play important structural and functional roles in maintaining the filtration barrier. Nephrotic syndrome results from a breakdown of the kidney filtration barrier and is associated with proteinuria, hyperlipidemia, and edema. Additionally, podocytes undergo changes 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. In cultured podocytes, the presence of free fatty acids (FFAs) associated with serum albumin stimulated macropinocytosis through a pathway that involves FFA receptors, the Gβ/Gγ complex, and RAC1. Moreover, mice with elevated levels of plasma FFAs 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 FFAs bound to albumin and respond by enhancing fluid-phase uptake. The response to FFAs may function in the development of nephrotic syndrome by amplifying the effects of proteinuria.

Authors

Jun-Jae Chung, Tobias B. Huber, Markus Gödel, George Jarad, Björn Hartleben, Christopher Kwoh, Alexander Keil, Aleksey Karpitskiy, Jiancheng Hu, Christine J. Huh, Marina Cella, Richard W. Gross, Jeffrey H. Miner, Andrey S. Shaw

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Figure 4

Podocyte macropinocytosis is stimulated by albumin-associated FFAs.

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Podocyte macropinocytosis is stimulated by albumin-associated FFAs. (A) ...
(A) Podocytes were incubated with 7.5% BSA or FFA-free BSA in the presence of FITC-dextran for 30 minutes and analyzed by flow cytometry. (B) Podocytes were incubated with 7.5% BSA, BSA lipid extract, or HSA lipid extract in the presence of FITC-dextran for 30 minutes and analyzed by flow cytometry. (C) Podocytes were incubated with increasing concentrations (1 or 10 μM) of FFAs in the presence of FITC-dextran for 30 minutes and analyzed by flow cytometry. (D) Podocytes were incubated with individual FFAs (2 μM) or a mixture of the FFAs (2 μM each) in the presence of FITC-dextran for 30 minutes and analyzed by flow cytometry. All results are shown as the fold change in mean fluorescence intensity. Data represent the mean ± SD of 3 independent experiments analyzed by ANOVA, followed by Bonferroni’s post-hoc analysis. *P ≤ 0.05; **P ≤ 0.01.