气候变化领域集成服务门户(CCPortal): Kidney intercalated cells and the transcription factor FOXi1 drive cystogenesis in tuberous sclerosis complex

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DOI	10.1073/pnas.2020190118
	Kidney intercalated cells and the transcription factor FOXi1 drive cystogenesis in tuberous sclerosis complex
	Barone S.; Zahedi K.; Brooks M.; Henske E.P.; Yang Y.; Zhang E.; Bissler J.J.; Yu J.J.; Soleimani M.
发表日期	2021
ISSN	00278424
卷号	118 期号:6
英文摘要	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. © This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
英文关键词	Cortical collecting duct; Cysts; H+-ATPase; Intercalated cells; Prorenin receptor
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180725
作者单位	Department of Medicine, University of New Mexico, Health Sciences Center, Albuquerque, NM 87131, United States; Research Services, Veterans Healthcare Medical Center, Albuquerque, NM 87108, United States; Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, United States; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, United States; Biomedical Research and Integrative Neuroscience (BRaIN) Imaging Center, University of New Mexico, Health Sciences Center, Albuquerque, NM 87131, United States; Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, NM 87106, United States; Department of Pediatrics, University of Tennessee Health Science Center, Le Bonheur Children's Hospital, Memphis, TN 38103, United States; Department of Pediatrics, St. Jude Children's Research Hospital, Memphis, TN 38105, United States
推荐引用方式 GB/T 7714	Barone S.,Zahedi K.,Brooks M.,et al. Kidney intercalated cells and the transcription factor FOXi1 drive cystogenesis in tuberous sclerosis complex[J],2021,118(6).
APA	Barone S..,Zahedi K..,Brooks M..,Henske E.P..,Yang Y..,...&Soleimani M..(2021).Kidney intercalated cells and the transcription factor FOXi1 drive cystogenesis in tuberous sclerosis complex.Proceedings of the National Academy of Sciences of the United States of America,118(6).
MLA	Barone S.,et al."Kidney intercalated cells and the transcription factor FOXi1 drive cystogenesis in tuberous sclerosis complex".Proceedings of the National Academy of Sciences of the United States of America 118.6(2021).