Grahammer, Florian, Ramakrishnan, Suresh K., Rinschen, Markus M., Larionov, Alexey A., Syed, Maryam, Khatib, Hazim, Roerden, Malte, Sass, Joern Oliver, Helmstaedter, Martin, Osenberg, Dorothea, Kuehne, Lucas, Kretz, Oliver, Wanner, Nicola, Jouret, Francois, Benzing, Thomas, Artunc, Ferruh, Huber, Tobias B. ORCID: 0000-0001-7175-5062 and Theilig, Franziska (2017). mTOR Regulates Endocytosis and Nutrient Transport in Proximal Tubular Cells. J. Am. Soc. Nephrol., 28 (1). S. 230 - 242. WASHINGTON: AMER SOC NEPHROLOGY. ISSN 1533-3450

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Grahammer, FlorianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ramakrishnan, Suresh K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rinschen, Markus M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Larionov, Alexey A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Syed, MaryamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Khatib, HazimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Roerden, MalteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sass, Joern OliverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Helmstaedter, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Osenberg, DorotheaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kuehne, LucasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kretz, OliverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wanner, NicolaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jouret, FrancoisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Benzing, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Artunc, FerruhUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Huber, Tobias B.UNSPECIFIEDorcid.org/0000-0001-7175-5062UNSPECIFIED
Theilig, FranziskaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-243677
DOI: 10.1681/ASN.2015111224
Journal or Publication Title: J. Am. Soc. Nephrol.
Volume: 28
Number: 1
Page Range: S. 230 - 242
Date: 2017
Publisher: AMER SOC NEPHROLOGY
Place of Publication: WASHINGTON
ISSN: 1533-3450
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
ANGIOTENSIN-II; KIDNEY; PHOSPHORYLATION; COTRANSPORTER; SIROLIMUS; DISEASE; COMPLEX; TRANSPLANTATION; RAPAMYCIN; NEPHRONMultiple languages
Urology & NephrologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/24367

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