Logo image
Back
Ganetespib limits ciliation and cystogenesis in autosomal-dominant polycystic kidney disease (ADPKD)
Journal article   Open access   Peer reviewed

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

Anna S Nikonova, Alexander Y Deneka, Anna A Kiseleva, Vladislav Korobeynikov, Anna Gaponova, Ilya G Serebriiskii, Meghan C Kopp, Harvey H Hensley, Tamina N Seeger-Nukpezah, Stefan Somlo, …
The FASEB journal, v 32(5), pp 2735-2746
May 2018
DOI: https://doi.org/10.1096/fj.201700909R
PMID: 29401581
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1096/fj.201700909rView
Published, Version of Record (VoR)Open Access (License Unspecified),  Open
url
https://doi.org/10.1096/fj.201700909RView
Published, Version of Record (VoR) Open

Abstract

Animals Aurora Kinase A - genetics Aurora Kinase A - metabolism Cilia - genetics Cilia - metabolism Disease Models, Animal HSP90 Heat-Shock Proteins - antagonists & inhibitors HSP90 Heat-Shock Proteins - genetics HSP90 Heat-Shock Proteins - metabolism Humans Mice Mice, Knockout NIMA-Related Kinases - genetics NIMA-Related Kinases - metabolism Polycystic Kidney, Autosomal Dominant - drug therapy Polycystic Kidney, Autosomal Dominant - genetics Polycystic Kidney, Autosomal Dominant - metabolism Protein-Serine-Threonine Kinases - genetics Protein-Serine-Threonine Kinases - metabolism Pyruvate Dehydrogenase (Acetyl-Transferring) Kinase Triazoles - pharmacology
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 function of the polycystins (encoded by PKD1 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, a glycolysis inhibitor showing some promise for ADPKD. These studies identify a new biologic activity for HSP90 and support a cilia-based mechanism for cyst repression.-Nikonova, A. S., Deneka, A. Y., Kiseleva, A. A., Korobeynikov, V., Gaponova, A., Serebriiskii, I. G., Kopp, M. C., Hensley, H. H., Seeger-Nukpezah, T. N., Somlo, S., Proia, D. A., Golemis, E. A. Ganetespib limits ciliation and cystogenesis in autosomal-dominant polycystic kidney disease (ADPKD).

Metrics

8 Record Views
30 citations in Web of Science
30 citations in Scopus

Details

UN Sustainable Development Goals (SDGs)

This publication has contributed to the advancement of the following goals:

#3 Good Health and Well-Being

InCites Highlights

Data related to this publication, from InCites Benchmarking & Analytics tool:

Collaboration types
Industry collaboration
Domestic collaboration
International collaboration
Web of Science research areas
Biochemistry & Molecular Biology
Biology
Cell Biology
Logo image