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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 L, 2017. "microRNA-17 family promotes polycystic kidney disease progression through modulation of mitochondrial metabolism," Nature Communications, Nature, vol. 8(1), pages 1-15, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14395
    DOI: 10.1038/ncomms14395
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    Cited by:

    1. Ronak Lakhia & Harini Ramalingam & Chun-Mien Chang & Patricia Cobo-Stark & Laurence Biggers & Andrea Flaten & Jesus Alvarez & Tania Valencia & Darren P. Wallace & Edmund C. Lee & Vishal Patel, 2022. "PKD1 and PKD2 mRNA cis-inhibition drives polycystic kidney disease progression," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Laura Onuchic & Valeria Padovano & Giorgia Schena & Vanathy Rajendran & Ke Dong & Xiaojian Shi & Raj Pandya & Victoria Rai & Nikolay P. Gresko & Omair Ahmed & TuKiet T. Lam & Weiwei Wang & Hongying Sh, 2023. "The C-terminal tail of polycystin-1 suppresses cystic disease in a mitochondrial enzyme-dependent fashion," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    3. Rebecca V Walker & Qin Yao & Hangxue Xu & Anthony Maranto & Kristen F Swaney & Sreekumar Ramachandran & Rong Li & Laura Cassina & Brian M Polster & Patricia Outeda & Alessandra Boletta & Terry Watnick, 2023. "Fibrocystin/Polyductin releases a C-terminal fragment that translocates into mitochondria and suppresses cystogenesis," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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