mTOR Regulates Endocytosis and Nutrient Transport in Proximal Tubular Cells

• Published in: Journal of the American Society of Nephrology Vol. 28; no. 1; pp. 230 - 241
• Main Authors: Grahammer, Florian, Ramakrishnan, Suresh K, Rinschen, Markus M, Larionov, Alexey A, Syed, Maryam, Khatib, Hazim, Roerden, Malte, Sass, Jörn Oliver, Helmstaedter, Martin, Osenberg, Dorothea, Kühne, Lucas, Kretz, Oliver, Wanner, Nicola, Jouret, Francois, Benzing, Thomas, Artunc, Ferruh, Huber, Tobias B, Theilig, Franziska
• Format: Journal Article Web Resource
• Language: English
• Published: United States Lippincott Williams and Wilkins 01-01-2017; American Society of Nephrology
• Subjects: albuminuria; Anatomie (cytologie, histologie, embryologie...) & physiologie; Anatomy (cytology, histology, embryology...) & physiology; Animals; Basic Research; endocytosis; Endocytosis - physiology; epithelial transport; Kidney Tubules, Proximal - cytology; Kidney Tubules, Proximal - metabolism; Life sciences; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Mice; mTOR; Multiprotein Complexes - physiology; Protein Transport; proteomics; proximal tubule; Sciences du vivant; TOR Serine-Threonine Kinases - physiology; mTOR; albuminuria; endocytosis; epithelial transport; proteomics; proximal tubule
• ISSN: 1046-6673; 1533-3450; 1533-3450
• DOI: 10.1681/asn.2015111224

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.