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J Biol Chem. 2014 Jun 20;289(25):17454-67. doi: 10.1074/jbc.M114.568998. Epub 2014 May 9.

Reduction of proteinuria through podocyte alkalinization.

Author information

1
From the Department of Medicine, Rush University Medical Center, Chicago, Illinois 60035.
2
the Department of Medicine, Division of Nephrology and Hypertension, University of Miami Miller School of Medicine, Miami, Florida 33136.
3
the Division of Nephrology and Program in Glomerular Disease, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02129.
4
the Renal Division, University Hospital Freiburg, 79106 Freiburg, Germany.
5
the Renal Division, University Hospital Freiburg, 79106 Freiburg, Germany, the BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs University, 79106 Freiburg, Germany.
6
the Department of Medicine, Division of Clinical Pharmacology, University of Miami Miller School of Medicine, Miami, Florida 33136.
7
the Department of Biochemistry, University of Texas Health Science Center, San Antonio, Texas 78229, and.
8
the Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria.
9
From the Department of Medicine, Rush University Medical Center, Chicago, Illinois 60035, jochen_reiser@rush.edu.

Abstract

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.

KEYWORDS:

Cell pH; Glutamine; Lipopolysaccharide (LPS); Metabolism; Podocyte

PMID:
24817115
PMCID:
PMC4067184
DOI:
10.1074/jbc.M114.568998
[Indexed for MEDLINE]
Free PMC Article

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