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Nat Commun. 2017 Feb 16;8:14395. doi: 10.1038/ncomms14395.

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

Author information

1
Department of Internal Medicine and Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
2
Regulus Therapeutics Inc., San Diego, California 92121, USA.
3
Department of Medicine and Division of Nephrology, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA.
4
Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
5
Department of Internal Medicine and Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
6
Department of Nephrology and Hypertension, Mayo College of Medicine, Rochester, Minnesota 55905, USA.
7
Molecular Genetics and Development, Institut de Recherches Cliniques de Montreal, Universite de Montreal, Faculte de Medecine, Montréal, Québec H2W 1R7, Canada.
8
Department of Medicine and the Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.

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.

PMID:
28205547
PMCID:
PMC5316862
DOI:
10.1038/ncomms14395
[Indexed for MEDLINE]
Free PMC Article

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