Universität zu Köln

Nikonova, Anna S., Deneka, Alexander Y., Kiseleva, Anna A., Korobeynikov, Vladislav ORCID: 0000-0002-9127-292X, Gaponova, Anna, Serebriiskii, Ilya G., Kopp, Meghan C., Hensley, Harvey H., Seeger-Nukpezah, Tamina N., Somlo, Stefan, Proia, David A. and Golemis, Erica A. (2018). Ganetespib limits ciliation and cystogenesis in autosomal-dominant polycystic kidney disease (ADPKD). Faseb J., 32 (5). S. 2735 - 2747. BETHESDA: FEDERATION AMER SOC EXP BIOL. ISSN 1530-6860

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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-n-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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Nikonova, Anna S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Deneka, Alexander Y. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kiseleva, Anna A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Korobeynikov, Vladislav UNSPECIFIED orcid.org/0000-0002-9127-292X UNSPECIFIED Gaponova, Anna UNSPECIFIED UNSPECIFIED UNSPECIFIED Serebriiskii, Ilya G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kopp, Meghan C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hensley, Harvey H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Seeger-Nukpezah, Tamina N. UNSPECIFIED UNSPECIFIED UNSPECIFIED Somlo, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Proia, David A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Golemis, Erica A. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-187739
DOI:	10.1096/fj.201700909R
Journal or Publication Title:	Faseb J.
Volume:	32
Number:	5
Page Range:	S. 2735 - 2747
Date:	2018
Publisher:	FEDERATION AMER SOC EXP BIOL
Place of Publication:	BETHESDA
ISSN:	1530-6860
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CYST GROWTH; RENAL CYSTOGENESIS; PROTEIN-KINASE; MOUSE MODEL; CELL-CYCLE; AURORA-A; CILIOGENESIS; INHIBITION; ACTIVATION; CANCER Multiple languages Biochemistry & Molecular Biology; Biology; Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/18773