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FASEB J. 2018 May;32(5):2735-2746. doi: 10.1096/fj.201700909R. Epub 2018 Jan 10.

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

Author information

1
Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
2
Kazan Federal University, Kazan, Russia.
3
Department of Pathology and Cell Biology, Columbia University, New York, New York, USA.
4
Laboratory of Genome Engineering, Moscow Institute of Physics and Technology, Dolgoprudny, Russia.
5
Immanuel Kant Baltic Federal University, Konigsberg, Russia.
6
Cancer Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA.
7
Department I of Internal Medicine and Center for Integrated Oncology, University of Cologne, Cologne, Germany.
8
Departments of Internal Medicine and Genetics, Yale School of Medicine, New Haven, Connecticut, USA; and.
9
Synta Pharmaceuticals Corporation, Lexington, Massachusetts, USA.

Abstract

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).

KEYWORDS:

PKD1; cilia; heat shock protein 90; polycystins; renal cyst

PMID:
29401581
PMCID:
PMC5901382
DOI:
10.1096/fj.201700909R
[Indexed for MEDLINE]
Free PMC Article

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