title: microRNA-17 family promotes polycystic kidney disease progression through modulation of mitochondrial metabolism.
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.
authors.affiliation: Department of Internal Medicine and Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Sachin
authors.initials: S
authors.lastname: Hajarnis
authors.affiliation: Department of Internal Medicine and Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Ronak
authors.initials: R
authors.lastname: Lakhia
authors.affiliation: Department of Internal Medicine and Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Matanel
authors.initials: M
authors.lastname: Yheskel
authors.affiliation: Department of Internal Medicine and Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Darren
authors.initials: D
authors.lastname: Williams
authors.affiliation: Regulus Therapeutics Inc., San Diego, California 92121, USA.
authors.forename: Mehran
authors.initials: M
authors.lastname: Sorourian
authors.affiliation: Regulus Therapeutics Inc., San Diego, California 92121, USA.
authors.forename: Xueqing
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Medicine and Division of Nephrology, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA.
authors.forename: Karam
authors.initials: K
authors.lastname: Aboudehen
authors.affiliation: Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Shanrong
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Regulus Therapeutics Inc., San Diego, California 92121, USA.
authors.forename: Kara
authors.initials: K
authors.lastname: Kersjes
authors.affiliation: Regulus Therapeutics Inc., San Diego, California 92121, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Galasso
authors.affiliation: Regulus Therapeutics Inc., San Diego, California 92121, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: Regulus Therapeutics Inc., San Diego, California 92121, USA.
authors.forename: Vivek
authors.identifier: 0000-0003-0268-2642
authors.initials: V
authors.lastname: Kaimal
authors.affiliation: Regulus Therapeutics Inc., San Diego, California 92121, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Lockton
authors.affiliation: Regulus Therapeutics Inc., San Diego, California 92121, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Davis
authors.affiliation: Department of Internal Medicine and Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Flaten
authors.affiliation: Department of Internal Medicine and Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Johnson
authors.affiliation: Department of Internal Medicine and Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: William L
authors.identifier: 0000-0001-9950-1435
authors.initials: WL
authors.lastname: Holland
authors.affiliation: Department of Internal Medicine and Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Kusminski
authors.affiliation: Department of Internal Medicine and Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Philipp E
authors.identifier: 0000-0003-0680-3392
authors.initials: PE
authors.lastname: Scherer
authors.affiliation: Department of Nephrology and Hypertension, Mayo College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Harris
authors.affiliation: Molecular Genetics and Development, Institut de Recherches Cliniques de Montreal, Universite de Montreal, Faculte de Medecine, Montréal, Québec H2W 1R7, Canada.
authors.forename: Marie
authors.initials: M
authors.lastname: Trudel
authors.affiliation: Department of Medicine and the Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
authors.forename: Darren P
authors.initials: DP
authors.lastname: Wallace
authors.affiliation: Department of Medicine and Division of Nephrology, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Igarashi
authors.affiliation: Regulus Therapeutics Inc., San Diego, California 92121, USA.
authors.forename: Edmund C
authors.initials: EC
authors.lastname: Lee
authors.affiliation: Regulus Therapeutics Inc., San Diego, California 92121, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Androsavich
authors.affiliation: Department of Internal Medicine and Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Vishal
authors.initials: V
authors.lastname: Patel
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000502:physiology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D017353:Gene Deletion; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D010766:Phosphorylation; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D015854:Up-Regulation
chemical_list: C524941:MIRN17 microRNA, human; C575895:MIRN17-92 microRNA, mouse; D035683:MicroRNAs; C543614:Mirn17 microRNA, mouse