Reduction of proteinuria through podocyte alkalinization

Mehmet M. Altintas, Kumiko Moriwaki, Changli Wei, Clemens C. Möller, Jan Flesche, Jing Li, Suma Yaddanapudi, Mohd Hafeez Faridi, Markus Gödel, Tobias B. Huber, Richard A. Preston, Jean X. Jiang, Dontscho Kerjaschki, Sanja Sever, Jochen Reiser

Research output: Contribution to journalArticle

9 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)17454-17467
Number of pages14
JournalJournal of Biological Chemistry
Volume289
Issue number25
DOIs
StatePublished - Jun 20 2014

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Altintas, M. M., Moriwaki, K., Wei, C., Möller, C. C., Flesche, J., Li, J., Yaddanapudi, S., Faridi, M. H., Gödel, M., Huber, T. B., Preston, R. A., Jiang, J. X., Kerjaschki, D., Sever, S., & Reiser, J. (2014). Reduction of proteinuria through podocyte alkalinization. Journal of Biological Chemistry, 289(25), 17454-17467. https://doi.org/10.1074/jbc.M114.568998