Ganetespib limits ciliation and cystogenesis in autosomal-dominant polycystic kidney disease (ADPKD)
| Autor: | David A. Proia, Ilya G. Serebriiskii, Harvey Hensley, Erica A. Golemis, Meghan C. Kopp, Alexander Y. Deneka, Tamina Seeger-Nukpezah, Vladislav Korobeynikov, Anna S. Nikonova, Anna A. Kiseleva, Anna Gaponova, Stefan Somlo |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
NEK8 Ganetespib Autosomal dominant polycystic kidney disease Protein Serine-Threonine Kinases urologic and male genital diseases Biochemistry Pathogenesis 03 medical and health sciences Mice 0302 clinical medicine Genetics medicine Polycystic kidney disease Animals Humans NIMA-Related Kinases Cyst Cilia HSP90 Heat-Shock Proteins Molecular Biology Aurora Kinase A Mice Knockout PKD1 business.industry urogenital system Cilium Research Pyruvate Dehydrogenase Acetyl-Transferring Kinase Triazoles medicine.disease Polycystic Kidney Autosomal Dominant female genital diseases and pregnancy complications Disease Models Animal 030104 developmental biology 030220 oncology & carcinogenesis Cancer research business Biotechnology |
| Zdroj: | FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 32(5) |
| ISSN: | 1530-6860 |
| Popis: | 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). |
| Databáze: | OpenAIRE |
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