title: Reduction of proteinuria through podocyte alkalinization.
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.
authors.affiliation: From the Department of Medicine, Rush University Medical Center, Chicago, Illinois 60035.
authors.forename: Mehmet M
authors.initials: MM
authors.lastname: Altintas
authors.affiliation: the Department of Medicine, Division of Nephrology and Hypertension, University of Miami Miller School of Medicine, Miami, Florida 33136.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Moriwaki
authors.affiliation: From the Department of Medicine, Rush University Medical Center, Chicago, Illinois 60035.
authors.forename: Changli
authors.initials: C
authors.lastname: Wei
authors.affiliation: the Division of Nephrology and Program in Glomerular Disease, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02129.
authors.forename: Clemens C
authors.initials: CC
authors.lastname: Möller
authors.affiliation: the Division of Nephrology and Program in Glomerular Disease, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02129.
authors.forename: Jan
authors.initials: J
authors.lastname: Flesche
authors.affiliation: From the Department of Medicine, Rush University Medical Center, Chicago, Illinois 60035.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: the Division of Nephrology and Program in Glomerular Disease, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02129.
authors.forename: Suma
authors.initials: S
authors.lastname: Yaddanapudi
authors.affiliation: From the Department of Medicine, Rush University Medical Center, Chicago, Illinois 60035.
authors.forename: Mohd Hafeez
authors.initials: MH
authors.lastname: Faridi
authors.affiliation: the Renal Division, University Hospital Freiburg, 79106 Freiburg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Gödel
authors.affiliation: the Renal Division, University Hospital Freiburg, 79106 Freiburg, Germany, the BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs University, 79106 Freiburg, Germany.
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Huber
authors.affiliation: the Department of Medicine, Division of Clinical Pharmacology, University of Miami Miller School of Medicine, Miami, Florida 33136.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Preston
authors.affiliation: the Department of Biochemistry, University of Texas Health Science Center, San Antonio, Texas 78229, and.
authors.forename: Jean X
authors.initials: JX
authors.lastname: Jiang
authors.affiliation: the Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Dontscho
authors.initials: D
authors.lastname: Kerjaschki
authors.affiliation: the Division of Nephrology and Program in Glomerular Disease, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02129.
authors.forename: Sanja
authors.initials: S
authors.lastname: Sever
authors.affiliation: From the Department of Medicine, Rush University Medical Center, Chicago, Illinois 60035, jochen_reiser@rush.edu.
authors.forename: Jochen
authors.initials: J
authors.lastname: Reiser
mesh_terms: D000818:Animals; D001693:Biological Transport, Active / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006863:Hydrogen-Ion Concentration; D051379:Mice; D018345:Mice, Knockout; D050199:Podocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D011507:Proteinuria / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
keywords: Cell pH; Glutamine; Lipopolysaccharide (LPS); Metabolism; Podocyte