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Seeger-Nukpezah T , Proia DA , Egleston BL , Nikonova AS , Kent T , Cai KQ , Hensley HH , Ying W , Chimmanamada D , Serebriiskii IG , Golemis EA
Inhibiting the HSP90 chaperone slows cyst growth in a mouse model of autosomal dominant polycystic kidney disease
Proc Natl Acad Sci U S A. 2013 Jul 30;110(31) :12786-91
PMID: 23858461    PMCID: PMC3732984   
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Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is a progressive genetic syndrome with an incidence of 1:500 in the population, arising from inherited mutations in the genes for polycystic kidney disease 1 (PKD1) or polycystic kidney disease 2 (PKD2). Typical onset is in middle age, with gradual replacement of renal tissue with thousands of fluid-filled cysts, resulting in end-stage renal disease requiring dialysis or kidney transplantation. There currently are no approved therapies to slow or cure ADPKD. Mutations in the PKD1 and PKD2 genes abnormally activate multiple signaling proteins and pathways regulating cell proliferation, many of which we observe, through network construction, to be regulated by heat shock protein 90 (HSP90). Inhibiting HSP90 with a small molecule, STA-2842, induces the degradation of many ADPKD-relevant HSP90 client proteins in Pkd1(-/-) primary kidney cells and in vivo. Using a conditional Cre-mediated mouse model to inactivate Pkd1 in vivo, we find that weekly administration of STA-2842 over 10 wk significantly reduces initial formation of renal cysts and kidney growth and slows the progression of these phenotypes in mice with preexisting cysts. These improved disease phenotypes are accompanied by improved indicators of kidney function and reduced expression and activity of HSP90 clients and their effectors, with the degree of inhibition correlating with cystic expansion in individual animals. Pharmacokinetic analysis indicates that HSP90 is overexpressed and HSP90 inhibitors are selectively retained in cystic versus normal kidney tissue, analogous to the situation observed in solid tumors. These results provide an initial justification for evaluating HSP90 inhibitors as therapeutic agents for ADPKD.
Notes
Seeger-Nukpezah, Tamina Proia, David A Egleston, Brian L Nikonova, Anna S Kent, Tatiana Cai, Kathy Q Hensley, Harvey H Ying, Weiwen Chimmanamada, Dinesh Serebriiskii, Ilya G Golemis, Erica A United States Proceedings of the National Academy of Sciences of the United States of America Proc Natl Acad Sci U S A. 2013 Jul 30;110(31):12786-91. doi: 10.1073/pnas.1301904110. Epub 2013 Jul 15.