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J Am Soc Nephrol. 2017 Jan;28(1):230-241. doi: 10.1681/ASN.2015111224. Epub 2016 Jun 13.

mTOR Regulates Endocytosis and Nutrient Transport in Proximal Tubular Cells.

Author information

1
Department of Medicine IV, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
2
Institute of Anatomy, Department of Medicine, University of Fribourg, Fribourg, Switzerland.
3
Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
4
Department of Medical IV, Sektion Nieren- und Hochdruckkrankheiten, University of Tübingen, Tübingen, Germany.
5
Bioanalytics and Biochemistry, Department of Natural Sciences, Bonn Rhein Sieg University of Applied Sciences, Rheinbach, Germany.
6
Division of Clinical Chemistry and Biochemistry and Children's Research Centre, University Children's Hospital Zürich, Zurich, Switzerland.
7
Groupe Interdisciplinaire de Génoprotéomique Appliquée, Cardiovascular Sciences, University of Liège, Liege, Belgium; and.
8
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.
9
BIOSS, Centre for Biological Signalling Studies and.
10
FRIAS, Freiburg Institute for Advanced Studies and ZBSA, Center for Biological System Analysis, Albert Ludwigs University of Freiburg, Freiburg, Germany.
11
Institute of Anatomy, Department of Medicine, University of Fribourg, Fribourg, Switzerland; franziska.theilig@unifr.ch tobias.huber@uniklinik-freiburg.de.

Abstract

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.

KEYWORDS:

albuminuria; endocytosis; epithelial transport; mTOR; proteomics; proximal tubule

Comment in

PMID:
27297946
PMCID:
PMC5198276
DOI:
10.1681/ASN.2015111224
[Indexed for MEDLINE]
Free PMC Article

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