Metabolism
Reduction of Proteinuria through Podocyte Alkalinization*

https://doi.org/10.1074/jbc.M114.568998Get rights and content
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Podocytes are highly differentiated cells and critical elements for the filtration barrier of the kidney. Loss of their foot process (FP) architecture (FP effacement) results in urinary protein loss. Here we show a novel role for the neutral amino acid glutamine in structural and functional regulation of the kidney filtration barrier. Metabolic flux analysis of cultured podocytes using genetic, toxic, and immunologic injury models identified increased glutamine utilization pathways. We show that glutamine uptake is increased in diseased podocytes to couple nutrient support to increased demand during the disease state of FP effacement. This feature can be utilized to transport increased amounts of glutamine into damaged podocytes. The availability of glutamine determines the regulation of podocyte intracellular pH (pHi). Podocyte alkalinization reduces cytosolic cathepsin L protease activity and protects the podocyte cytoskeleton. Podocyte glutamine supplementation reduces proteinuria in LPS-treated mice, whereas acidification increases glomerular injury. In summary, our data provide a metabolic opportunity to combat urinary protein loss through modulation of podocyte amino acid utilization and pHi.

Cell pH
Glutamine
Lipopolysaccharide (LPS)
Metabolism
Podocyte

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*

This work was supported, in whole or in part, by National Institutes of Health Grant DK073495 (to J. R.). This work was also supported by funds from the Ajinomoto Amino Acid Research Program (to J. R.) and Welch Foundation Grant AQ-1507 (to J. X. J.). D. Reiser is an inventor of issued and pending patents related to proteinuric kidney disease diagnostic and treatment, and he stands to gain royalties from future commercializations.

This article contains supplemental Tables S1–S4 and Figs. S1–S4.