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Ganetespib limits ciliation and cystogenesis in autosomal-dominant polycystic kidney disease (ADPKD)

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dc.contributor.author Proia D.
dc.contributor.author Golemis E.
dc.date.accessioned 2019-01-22T20:37:59Z
dc.date.available 2019-01-22T20:37:59Z
dc.date.issued 2018
dc.identifier.issn 0892-6638
dc.identifier.uri https://dspace.kpfu.ru/xmlui/handle/net/148056
dc.description.abstract © 2018 FASEB. Autosomal-dominant polycystic kidney disease (ADPKD) is associated with progressive formation of renal cysts, kidney enlargement, hypertension, and typically end-stage renal disease. In ADPKD, inherited mutations disrupt functionofthe polycystins (encoded byPKD1 and PKD2), thus causing loss of a cyst-repressive signal emanating from the renal cilium. Genetic studies have suggested ciliary maintenance is essential for ADPKD pathogenesis. Heat shock protein 90 (HSP90) clients include multiple proteins linked to ciliary maintenance. We determined that ganetespib, a clinical HSP90 inhibitor, inhibited proteasomal repression of NEK8 and the Aurora-A activator trichoplein, rapidly activating Aurora-A kinase and causing ciliary loss in vitro. Using conditional mouse models for ADPKD, we performed long-term (10 or 50 wk) dosing experiments that demonstrated HSP90 inhibition caused durable in vivo loss of cilia, controlled cystic growth, and ameliorated symptoms induced by loss of Pkd1 or Pkd2.Ganetespib efficacy was not increased by combination with 2-deoxy-D-glucose, aglycolysis inhibitor showing some promise for ADPKD. These studies identify a new biologic activity for HSP90 and support a cilia-based mechanism for cyst repression.
dc.relation.ispartofseries FASEB Journal
dc.subject Cilia
dc.subject Heat shock protein 90
dc.subject PKD1
dc.subject Polycystins
dc.subject Renal cyst
dc.title Ganetespib limits ciliation and cystogenesis in autosomal-dominant polycystic kidney disease (ADPKD)
dc.type Article
dc.relation.ispartofseries-issue 5
dc.relation.ispartofseries-volume 32
dc.collection Публикации сотрудников КФУ
dc.relation.startpage 2735
dc.source.id SCOPUS08926638-2018-32-5-SID85048613706


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  • Публикации сотрудников КФУ Scopus [24551]
    Коллекция содержит публикации сотрудников Казанского федерального (до 2010 года Казанского государственного) университета, проиндексированные в БД Scopus, начиная с 1970г.

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