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Open AccessArticle

Tuberous Sclerosis Complex Axis Controls Renal Extracellular Vesicle Production and Protein Content

1
Department of Clinical Biochemistry, College of Medicine & Health Sciences, Sultan Qaboos University, Muscat 123, Oman
2
Department of Pediatrics, University of Tennessee Health Science Center and Le Bonheur Children’s Hospital, Memphis, TN 38103, USA
3
Children’s Foundation Research Institute (CFRI), Le Bonheur Children’s Hospital, Memphis, TN 38103, USA
4
Molecular Bioinformatics Center, University of Tennessee Health Science Center Memphis, TN 38103, USA
5
Department of Veterinary Pathology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
6
Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
7
Department of Pediatrics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(5), 1729; https://doi.org/10.3390/ijms21051729
Received: 4 February 2020 / Revised: 28 February 2020 / Accepted: 29 February 2020 / Published: 3 March 2020
(This article belongs to the Section Biochemistry)
The tuberous sclerosis complex (Tsc) proteins regulate the conserved mTORC1 growth regulation pathway. We identified that loss of the Tsc2 gene in mouse inner medullary collecting duct (mIMCD) cells induced a greater than two-fold increase in extracellular vesicle (EV) production compared to the same cells having an intact Tsc axis. We optimized EV isolation using a well-established size exclusion chromatography method to produce high purity EVs. Electron microscopy confirmed the purity and spherical shape of EVs. Both tunable resistive pulse sensing (TRPS) and dynamic light scattering (DLS) demonstrated that the isolated EVs possessed a heterogenous size distribution. Approximately 90% of the EVs were in the 100–250 nm size range, while approximately 10% had a size greater than 250 nm. Western blot analysis using proteins isolated from the EVs revealed the cellular proteins Alix and TSG101, the transmembrane proteins CD63, CD81, and CD9, and the primary cilia Hedgehog signaling-related protein Arl13b. Proteomic analysis of EVs identified a significant difference between the Tsc2-intact and Tsc2-deleted cell that correlated well with the increased production. The EVs may be involved in tissue homeostasis and cause disease by overproduction and altered protein content. The EVs released by renal cyst epithelia in TSC complex may serve as a tool to discover the mechanism of TSC cystogenesis and in developing potential therapeutic strategies. View Full-Text
Keywords: TSC complex; extracellular vesicles (EVs); mTORC1; renal cyst TSC complex; extracellular vesicles (EVs); mTORC1; renal cyst
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MDPI and ACS Style

Zadjali, F.; Kumar, P.; Yao, Y.; Johnson, D.; Astrinidis, A.; Vogel, P.; Gross, K.W.; Bissler, J.J. Tuberous Sclerosis Complex Axis Controls Renal Extracellular Vesicle Production and Protein Content. Int. J. Mol. Sci. 2020, 21, 1729. https://doi.org/10.3390/ijms21051729

AMA Style

Zadjali F, Kumar P, Yao Y, Johnson D, Astrinidis A, Vogel P, Gross KW, Bissler JJ. Tuberous Sclerosis Complex Axis Controls Renal Extracellular Vesicle Production and Protein Content. International Journal of Molecular Sciences. 2020; 21(5):1729. https://doi.org/10.3390/ijms21051729

Chicago/Turabian Style

Zadjali, Fahad; Kumar, Prashant; Yao, Ying; Johnson, Daniel; Astrinidis, Aristotelis; Vogel, Peter; Gross, Kenneth W.; Bissler, John J. 2020. "Tuberous Sclerosis Complex Axis Controls Renal Extracellular Vesicle Production and Protein Content" Int. J. Mol. Sci. 21, no. 5: 1729. https://doi.org/10.3390/ijms21051729

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