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Kidney intercalated cells and the transcription factor FOXi1 drive cystogenesis in tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is caused by mutations in either TSC1 or TSC2 genes and affects multiple organs, including kidney, lung, and brain. In the kidney, TSC presents with the enlargement of benign tumors (angiomyolipomata) and cysts, which eventually leads to kidney failure. The factors p...

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Autores principales: Barone, Sharon, Zahedi, Kamyar, Brooks, Marybeth, Henske, Elizabeth P., Yang, Yirong, Zhang, Erik, Bissler, John J., Yu, Jane J., Soleimani, Manoocher
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017711/
https://www.ncbi.nlm.nih.gov/pubmed/33536341
http://dx.doi.org/10.1073/pnas.2020190118
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author Barone, Sharon
Zahedi, Kamyar
Brooks, Marybeth
Henske, Elizabeth P.
Yang, Yirong
Zhang, Erik
Bissler, John J.
Yu, Jane J.
Soleimani, Manoocher
author_facet Barone, Sharon
Zahedi, Kamyar
Brooks, Marybeth
Henske, Elizabeth P.
Yang, Yirong
Zhang, Erik
Bissler, John J.
Yu, Jane J.
Soleimani, Manoocher
author_sort Barone, Sharon
collection PubMed
description Tuberous sclerosis complex (TSC) is caused by mutations in either TSC1 or TSC2 genes and affects multiple organs, including kidney, lung, and brain. In the kidney, TSC presents with the enlargement of benign tumors (angiomyolipomata) and cysts, which eventually leads to kidney failure. The factors promoting cyst formation and tumor growth in TSC are incompletely understood. Here, we report that mice with principal cell-specific inactivation of Tsc1 develop numerous cortical cysts, which are overwhelmingly composed of hyperproliferating A-intercalated (A-IC) cells. RNA sequencing and confirmatory expression studies demonstrated robust expression of Forkhead Transcription Factor 1 (Foxi1) and its downstream targets, apical H(+)-ATPase and cytoplasmic carbonic anhydrase 2 (CAII), in cyst epithelia in Tsc1 knockout (KO) mice but not in Pkd1 mutant mice. In addition, the electrogenic 2Cl(−)/H(+) exchanger (CLC-5) is significantly up-regulated and shows remarkable colocalization with H(+)-ATPase on the apical membrane of cyst epithelia in Tsc1 KO mice. Deletion of Foxi1, which is vital to intercalated cells viability and H(+)-ATPase expression, completely abrogated the cyst burden in Tsc1 KO mice, as indicated by MRI images and histological analysis in kidneys of Foxi1/Tsc1 double-knockout (dKO) mice. Deletion of CAII, which is critical to H(+)-ATPase activation, caused significant reduction in cyst burden and increased life expectancy in CAII/Tsc1 dKO mice vs. Tsc1 KO mice. We propose that intercalated cells and their acid/base/electrolyte transport machinery (H(+)-ATPase/CAII/CLC-5) are critical to cystogenesis, and their inhibition or inactivation is associated with significant protection against cyst generation and/or enlargement in TSC.
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spelling pubmed-80177112021-04-12 Kidney intercalated cells and the transcription factor FOXi1 drive cystogenesis in tuberous sclerosis complex Barone, Sharon Zahedi, Kamyar Brooks, Marybeth Henske, Elizabeth P. Yang, Yirong Zhang, Erik Bissler, John J. Yu, Jane J. Soleimani, Manoocher Proc Natl Acad Sci U S A Biological Sciences Tuberous sclerosis complex (TSC) is caused by mutations in either TSC1 or TSC2 genes and affects multiple organs, including kidney, lung, and brain. In the kidney, TSC presents with the enlargement of benign tumors (angiomyolipomata) and cysts, which eventually leads to kidney failure. The factors promoting cyst formation and tumor growth in TSC are incompletely understood. Here, we report that mice with principal cell-specific inactivation of Tsc1 develop numerous cortical cysts, which are overwhelmingly composed of hyperproliferating A-intercalated (A-IC) cells. RNA sequencing and confirmatory expression studies demonstrated robust expression of Forkhead Transcription Factor 1 (Foxi1) and its downstream targets, apical H(+)-ATPase and cytoplasmic carbonic anhydrase 2 (CAII), in cyst epithelia in Tsc1 knockout (KO) mice but not in Pkd1 mutant mice. In addition, the electrogenic 2Cl(−)/H(+) exchanger (CLC-5) is significantly up-regulated and shows remarkable colocalization with H(+)-ATPase on the apical membrane of cyst epithelia in Tsc1 KO mice. Deletion of Foxi1, which is vital to intercalated cells viability and H(+)-ATPase expression, completely abrogated the cyst burden in Tsc1 KO mice, as indicated by MRI images and histological analysis in kidneys of Foxi1/Tsc1 double-knockout (dKO) mice. Deletion of CAII, which is critical to H(+)-ATPase activation, caused significant reduction in cyst burden and increased life expectancy in CAII/Tsc1 dKO mice vs. Tsc1 KO mice. We propose that intercalated cells and their acid/base/electrolyte transport machinery (H(+)-ATPase/CAII/CLC-5) are critical to cystogenesis, and their inhibition or inactivation is associated with significant protection against cyst generation and/or enlargement in TSC. National Academy of Sciences 2021-02-09 2021-02-03 /pmc/articles/PMC8017711/ /pubmed/33536341 http://dx.doi.org/10.1073/pnas.2020190118 Text en Copyright © 2021 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Barone, Sharon
Zahedi, Kamyar
Brooks, Marybeth
Henske, Elizabeth P.
Yang, Yirong
Zhang, Erik
Bissler, John J.
Yu, Jane J.
Soleimani, Manoocher
Kidney intercalated cells and the transcription factor FOXi1 drive cystogenesis in tuberous sclerosis complex
title Kidney intercalated cells and the transcription factor FOXi1 drive cystogenesis in tuberous sclerosis complex
title_full Kidney intercalated cells and the transcription factor FOXi1 drive cystogenesis in tuberous sclerosis complex
title_fullStr Kidney intercalated cells and the transcription factor FOXi1 drive cystogenesis in tuberous sclerosis complex
title_full_unstemmed Kidney intercalated cells and the transcription factor FOXi1 drive cystogenesis in tuberous sclerosis complex
title_short Kidney intercalated cells and the transcription factor FOXi1 drive cystogenesis in tuberous sclerosis complex
title_sort kidney intercalated cells and the transcription factor foxi1 drive cystogenesis in tuberous sclerosis complex
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017711/
https://www.ncbi.nlm.nih.gov/pubmed/33536341
http://dx.doi.org/10.1073/pnas.2020190118
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