mTOR Regulates Endocytosis and Nutrient Transport in Proximal Tubular Cells.
Renal proximal tubular cells constantly recycle nutrients to ensure minimal loss of vital substrates into the urine. Although most of the transport mechanisms have been discovered at the molecular level, little is known about the factors regulating these processes. Here, we show that mTORC1 and mTORC2 specifically and synergistically regulate PTC endocytosis and transport processes. Using a conditional mouse genetic approach to disable nonredundant subunits of mTORC1, mTORC2, or both, we showed that mice lacking mTORC1 or mTORC1/mTORC2 but not mTORC2 alone develop a Fanconi-like syndrome of glucosuria, phosphaturia, aminoaciduria, low molecular weight proteinuria, and albuminuria. Interestingly, proteomics and phosphoproteomics of freshly isolated kidney cortex identified either reduced expression or loss of phosphorylation at critical residues of different classes of specific transport proteins. Functionally, this resulted in reduced nutrient transport and a profound perturbation of the endocytic machinery, despite preserved absolute expression of the main scavenger receptors, MEGALIN and CUBILIN. Our findings highlight a novel mTOR-dependent regulatory network for nutrient transport in renal proximal tubular cells.
Department of Medicine IV, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Florian
F
Grahammer
Institute of Anatomy, Department of Medicine, University of Fribourg, Fribourg, Switzerland.
Suresh K
SK
Ramakrishnan
Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
Markus M
MM
Rinschen
Institute of Anatomy, Department of Medicine, University of Fribourg, Fribourg, Switzerland.
Alexey A
AA
Larionov
Institute of Anatomy, Department of Medicine, University of Fribourg, Fribourg, Switzerland.
Maryam
M
Syed
Department of Medical IV, Sektion Nieren- und Hochdruckkrankheiten, University of Tübingen, Tübingen, Germany.
Hazim
H
Khatib
Department of Medical IV, Sektion Nieren- und Hochdruckkrankheiten, University of Tübingen, Tübingen, Germany.
Malte
M
Roerden
Bioanalytics and Biochemistry, Department of Natural Sciences, Bonn Rhein Sieg University of Applied Sciences, Rheinbach, Germany.|Division of Clinical Chemistry and Biochemistry and Children's Research Centre, University Children's Hospital Zürich, Zurich, Switzerland.
Jörn Oliver
JO
Sass
Department of Medicine IV, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Martin
M
Helmstaedter
Department of Medicine IV, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Dorothea
D
Osenberg
Department of Medicine IV, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Lucas
L
Kühne
Department of Medicine IV, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Oliver
O
Kretz
Department of Medicine IV, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Nicola
N
Wanner
Groupe Interdisciplinaire de Génoprotéomique Appliquée, Cardiovascular Sciences, University of Liège, Liege, Belgium; and.
Francois
F
Jouret
Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
Thomas
T
Benzing
Department of Medical IV, Sektion Nieren- und Hochdruckkrankheiten, University of Tübingen, Tübingen, Germany.
Ferruh
F
Artunc
Department of Medicine IV, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; franziska.theilig@unifr.ch tobias.huber@uniklinik-freiburg.de.|BIOSS, Centre for Biological Signalling Studies and.|FRIAS, Freiburg Institute for Advanced Studies and ZBSA, Center for Biological System Analysis, Albert Ludwigs University of Freiburg, Freiburg, Germany.
Tobias B
TB
Huber
Institute of Anatomy, Department of Medicine, University of Fribourg, Fribourg, Switzerland; franziska.theilig@unifr.ch tobias.huber@uniklinik-freiburg.de.
Franziska
F
Theilig
D000818:Animals; D004705:Endocytosis / Q000502:physiology*; D007687:Kidney Tubules, Proximal / Q000166:cytology* / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D046912:Multiprotein Complexes / Q000502:physiology*; D021381:Protein Transport; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*
D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases
albuminuria; endocytosis; epithelial transport; mTOR; proteomics; proximal tubule