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

Sachin Hajarnis, Ronak Lakhia, Matanel Yheskel, Darren Williams, Mehran Sorourian, Xueqing Liu, Karam Aboudehen, Shanrong Zhang, Kara Kersjes, Ryan Galasso, Jian Li, Vivek Kaimal, Steven Lockton, Scott Davis, Andrea Flaten, Joshua A. Johnson, William L. Holland, Christine M. Kusminski, Philipp E. Scherer, Peter C. Harris, Marie Trudel, Darren P. Wallace, Peter Igarashi, Edmund C. Lee, John R. Androsavich and Vishal Patel ()
Additional contact information
Sachin Hajarnis: University of Texas Southwestern Medical Center
Ronak Lakhia: University of Texas Southwestern Medical Center
Matanel Yheskel: University of Texas Southwestern Medical Center
Darren Williams: University of Texas Southwestern Medical Center
Mehran Sorourian: Regulus Therapeutics Inc.
Xueqing Liu: Regulus Therapeutics Inc.
Karam Aboudehen: University of Minnesota Medical School
Shanrong Zhang: Advanced Imaging Research Center, University of Texas Southwestern Medical Center
Kara Kersjes: Regulus Therapeutics Inc.
Ryan Galasso: Regulus Therapeutics Inc.
Jian Li: Regulus Therapeutics Inc.
Vivek Kaimal: Regulus Therapeutics Inc.
Steven Lockton: Regulus Therapeutics Inc.
Scott Davis: Regulus Therapeutics Inc.
Andrea Flaten: University of Texas Southwestern Medical Center
Joshua A. Johnson: University of Texas Southwestern Medical Center
William L. Holland: University of Texas Southwestern Medical Center
Christine M. Kusminski: University of Texas Southwestern Medical Center
Philipp E. Scherer: University of Texas Southwestern Medical Center
Peter C. Harris: Mayo College of Medicine
Marie Trudel: Molecular Genetics and Development, Institut de Recherches Cliniques de Montreal, Universite de Montreal, Faculte de Medecine
Darren P. Wallace: University of Kansas Medical Center
Peter Igarashi: University of Minnesota Medical School
Edmund C. Lee: Regulus Therapeutics Inc.
John R. Androsavich: Regulus Therapeutics Inc.
Vishal Patel: University of Texas Southwestern Medical Center

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/ncomms14395

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