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Tsc2 mutation induces renal tubular cell nonautonomous disease

TSC renal cystic disease is poorly understood and has no approved treatment. In a new principal cell-targeted murine model of Tsc cystic disease, the renal cystic epithelium is mostly composed of type A intercalated cells with an intact Tsc2 gene confirmed by sequencing, although these cells exhibit...

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Autores principales: Kumar, Prashant, Zadjali, Fahad, Yao, Ying, Johnson, Daniel, Siroky, Brian, Astrinidis, Aristotelis, Vogel, Peter, Gross, Kenneth W., Bissler, John J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Chongqing Medical University 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8720703/
https://www.ncbi.nlm.nih.gov/pubmed/35005118
http://dx.doi.org/10.1016/j.gendis.2021.03.010
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author Kumar, Prashant
Zadjali, Fahad
Yao, Ying
Johnson, Daniel
Siroky, Brian
Astrinidis, Aristotelis
Vogel, Peter
Gross, Kenneth W.
Bissler, John J.
author_facet Kumar, Prashant
Zadjali, Fahad
Yao, Ying
Johnson, Daniel
Siroky, Brian
Astrinidis, Aristotelis
Vogel, Peter
Gross, Kenneth W.
Bissler, John J.
author_sort Kumar, Prashant
collection PubMed
description TSC renal cystic disease is poorly understood and has no approved treatment. In a new principal cell-targeted murine model of Tsc cystic disease, the renal cystic epithelium is mostly composed of type A intercalated cells with an intact Tsc2 gene confirmed by sequencing, although these cells exhibit a Tsc-mutant disease phenotype. We used a newly derived targeted murine model in lineage tracing and extracellular vesicle (EV) characterization experiments and a cell culture model in EV characterization and cellular induction experiments to understand TSC cystogenesis. Using lineage tracing experiments, we found principal cells undergo clonal expansion but contribute very few cells to the cyst. We determined that cystic kidneys contain more interstitial EVs than noncystic kidneys, excrete fewer EVs in urine, and contain EVs in cyst fluid. Moreover, the loss of Tsc2 gene in EV-producing cells greatly changes the effect of EVs on renal tubular epithelium, such that the epithelium develops increased secretory and proliferative pathway activity. We demonstate that the mTORC1 pathway activity is independent form the EV production, and that the EV effects for a single cell line can vary significantly. TSC cystogenesis involves significant contribution from genetically intact cells conscripted to the mutant phenotype by mutant cell derived EVs.
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spelling pubmed-87207032022-01-07 Tsc2 mutation induces renal tubular cell nonautonomous disease Kumar, Prashant Zadjali, Fahad Yao, Ying Johnson, Daniel Siroky, Brian Astrinidis, Aristotelis Vogel, Peter Gross, Kenneth W. Bissler, John J. Genes Dis Full Length Article TSC renal cystic disease is poorly understood and has no approved treatment. In a new principal cell-targeted murine model of Tsc cystic disease, the renal cystic epithelium is mostly composed of type A intercalated cells with an intact Tsc2 gene confirmed by sequencing, although these cells exhibit a Tsc-mutant disease phenotype. We used a newly derived targeted murine model in lineage tracing and extracellular vesicle (EV) characterization experiments and a cell culture model in EV characterization and cellular induction experiments to understand TSC cystogenesis. Using lineage tracing experiments, we found principal cells undergo clonal expansion but contribute very few cells to the cyst. We determined that cystic kidneys contain more interstitial EVs than noncystic kidneys, excrete fewer EVs in urine, and contain EVs in cyst fluid. Moreover, the loss of Tsc2 gene in EV-producing cells greatly changes the effect of EVs on renal tubular epithelium, such that the epithelium develops increased secretory and proliferative pathway activity. We demonstate that the mTORC1 pathway activity is independent form the EV production, and that the EV effects for a single cell line can vary significantly. TSC cystogenesis involves significant contribution from genetically intact cells conscripted to the mutant phenotype by mutant cell derived EVs. Chongqing Medical University 2021-04-27 /pmc/articles/PMC8720703/ /pubmed/35005118 http://dx.doi.org/10.1016/j.gendis.2021.03.010 Text en © 2021 Chongqing Medical University. Production and hosting by Elsevier B.V. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Full Length Article
Kumar, Prashant
Zadjali, Fahad
Yao, Ying
Johnson, Daniel
Siroky, Brian
Astrinidis, Aristotelis
Vogel, Peter
Gross, Kenneth W.
Bissler, John J.
Tsc2 mutation induces renal tubular cell nonautonomous disease
title Tsc2 mutation induces renal tubular cell nonautonomous disease
title_full Tsc2 mutation induces renal tubular cell nonautonomous disease
title_fullStr Tsc2 mutation induces renal tubular cell nonautonomous disease
title_full_unstemmed Tsc2 mutation induces renal tubular cell nonautonomous disease
title_short Tsc2 mutation induces renal tubular cell nonautonomous disease
title_sort tsc2 mutation induces renal tubular cell nonautonomous disease
topic Full Length Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8720703/
https://www.ncbi.nlm.nih.gov/pubmed/35005118
http://dx.doi.org/10.1016/j.gendis.2021.03.010
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