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 & 6 others Marie Trudel, Darren P. Wallace, Peter Igarashi, Edmund C. Lee, John R. Androsavich, Vishal Patel

Research output: Contribution to journalArticle

38 Citations (Scopus)

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 ∼ 492 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.

Original languageEnglish (US)
Article number14395
JournalNature Communications
Volume8
DOIs
StatePublished - Feb 16 2017

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kidney diseases
Autosomal Dominant Polycystic Kidney
Polycystic Kidney Diseases
metabolism
cysts
MicroRNAs
Metabolism
progressions
Disease Progression
Cysts
Modulation
modulation
mice
kidneys
Growth
Cystic Kidney Diseases
Enzyme inhibition
deletion
phosphorylation
Oxidative Phosphorylation

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

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

In: Nature Communications, Vol. 8, 14395, 16.02.2017.

Research output: Contribution to journalArticle

Hajarnis, S, Lakhia, R, Yheskel, M, Williams, D, Sorourian, M, Liu, X, Aboudehen, K, Zhang, S, Kersjes, K, Galasso, R, Li, J, Kaimal, V, Lockton, S, Davis, S, Flaten, A, Johnson, JA, Holland, WL, Kusminski, CM, Scherer, PE, Harris, PC, Trudel, M, Wallace, DP, Igarashi, P, Lee, EC, Androsavich, JR & Patel, V 2017, 'MicroRNA-17 family promotes polycystic kidney disease progression through modulation of mitochondrial metabolism', Nature Communications, vol. 8, 14395. https://doi.org/10.1038/ncomms14395
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. / MicroRNA-17 family promotes polycystic kidney disease progression through modulation of mitochondrial metabolism. In: Nature Communications. 2017 ; Vol. 8.
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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 ∼ 492 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.",
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AU - Lakhia, Ronak

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AU - Sorourian, Mehran

AU - Liu, Xueqing

AU - Aboudehen, Karam

AU - Zhang, Shanrong

AU - Kersjes, Kara

AU - Galasso, Ryan

AU - Li, Jian

AU - Kaimal, Vivek

AU - Lockton, Steven

AU - Davis, Scott

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AU - Holland, William L.

AU - Kusminski, Christine M.

AU - Scherer, Philipp E.

AU - Harris, Peter C.

AU - Trudel, Marie

AU - Wallace, Darren P.

AU - Igarashi, Peter

AU - Lee, Edmund C.

AU - Androsavich, John R.

AU - Patel, Vishal

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N2 - 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 ∼ 492 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.

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