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

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

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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
Springer Nature
Chemistry; Biochemistry, Genetics and Molecular Biology; Physics and Astronomy
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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.