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

Anna S. Nikonova, Alexander Y. Deneka, Anna Kiseleva, Vladislav A. Korobeynikov, Anna V. Gaponova, Ilya G. Serebriiskii, Meghan C. Kopp, Harvey Hensley, Tamina N. Seeger-Nukpezah, Stefan Somlo, David A. Proia, Erica A. Golemis

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

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 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.

Original languageEnglish
Pages (from-to)2735-2746
Number of pages12
JournalFASEB Journal
Volume32
Issue number5
DOIs
StatePublished - May 2018

Keywords

  • Animals
  • Aurora Kinase A/genetics
  • Cilia/genetics
  • Disease Models, Animal
  • HSP90 Heat-Shock Proteins/antagonists & inhibitors
  • Humans
  • Mice
  • Mice, Knockout
  • NIMA-Related Kinases/genetics
  • Polycystic Kidney, Autosomal Dominant/drug therapy
  • Protein Serine-Threonine Kinases/genetics
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Triazoles/pharmacology

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