TY - JOUR
T1 - Ganetespib limits ciliation and cystogenesis in autosomal-dominant polycystic kidney disease (ADPKD)
AU - Nikonova, Anna S.
AU - Deneka, Alexander Y.
AU - Kiseleva, Anna
AU - Korobeynikov, Vladislav A.
AU - Gaponova, Anna V.
AU - Serebriiskii, Ilya G.
AU - Kopp, Meghan C.
AU - Hensley, Harvey
AU - Seeger-Nukpezah, Tamina N.
AU - Somlo, Stefan
AU - Proia, David A.
AU - Golemis, Erica A.
N1 - Publisher Copyright:
© 2018 FASEB.
PY - 2018/5
Y1 - 2018/5
N2 - 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.
AB - 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.
KW - Animals
KW - Aurora Kinase A/genetics
KW - Cilia/genetics
KW - Disease Models, Animal
KW - HSP90 Heat-Shock Proteins/antagonists & inhibitors
KW - Humans
KW - Mice
KW - Mice, Knockout
KW - NIMA-Related Kinases/genetics
KW - Polycystic Kidney, Autosomal Dominant/drug therapy
KW - Protein Serine-Threonine Kinases/genetics
KW - Pyruvate Dehydrogenase Acetyl-Transferring Kinase
KW - Triazoles/pharmacology
UR - http://www.scopus.com/inward/record.url?scp=85048613706&partnerID=8YFLogxK
U2 - 10.1096/fj.201700909R
DO - 10.1096/fj.201700909R
M3 - Article
C2 - 29401581
SN - 0892-6638
VL - 32
SP - 2735
EP - 2746
JO - FASEB Journal
JF - FASEB Journal
IS - 5
ER -