microRNA-17 family promotes polycystic kidney disease progression through modulation of mitochondrial metabolism.

Citation data:

Nature communications, ISSN: 2041-1723, Vol: 8, Page: 14395

Publication Year:
2017
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PMID:
28205547
DOI:
10.1038/ncomms14395
Author(s):
Hajarnis, Sachin, Lakhia, Ronak, Yheskel, Matanel, Williams, Darren, Sorourian, Mehran, Liu, Xueqing, Aboudehen, Karam, Zhang, Shanrong, Kersjes, Kara, Galasso, Ryan, Li, Jian, Kaimal, Vivek, Lockton, Steven, Davis, Scott, Flaten, Andrea, Johnson, Joshua A, Holland, William L, Kusminski, Christine M, Scherer, Philipp E, Harris, Peter C, Trudel, Marie, Wallace, Darren P, Igarashi, Peter, Lee, Edmund C, Androsavich, John R, Patel, Vishal Show More Hide
Publisher(s):
Springer Nature
Tags:
Chemistry, Biochemistry, Genetics and Molecular Biology, Physics and Astronomy
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article description
Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent genetic cause of renal failure. Here we identify miR-17 as a target for the treatment of ADPKD. We report that miR-17 is induced in kidney cysts of mouse and human ADPKD. Genetic deletion of the miR-17∼92 cluster inhibits cyst proliferation and PKD progression in four orthologous, including two long-lived, mouse models of ADPKD. Anti-miR-17 treatment attenuates cyst growth in short-term and long-term PKD mouse models. miR-17 inhibition also suppresses proliferation and cyst growth of primary ADPKD cysts cultures derived from multiple human donors. Mechanistically, c-Myc upregulates miR-17∼92 in cystic kidneys, which in turn aggravates cyst growth by inhibiting oxidative phosphorylation and stimulating proliferation through direct repression of Pparα. Thus, miR-17 family is a promising drug target for ADPKD, and miR-17-mediated inhibition of mitochondrial metabolism represents a potential new mechanism for ADPKD progression.

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