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; Vishal Patel

doi:10.1038/ncomms14395

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. HarrisMarie Trudel, Darren P. Wallace, Peter Igarashi, Edmund C. Lee, John R. Androsavich, Vishal Patel

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139 Scopus citations

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 language	English (US)
Article number	14395
Journal	Nature communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms14395
State	Published - Feb 16 2017

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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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, J. A., Holland, W. L., Kusminski, C. M., Scherer, P. E., ... Patel, V. (2017). MicroRNA-17 family promotes polycystic kidney disease progression through modulation of mitochondrial metabolism. Nature communications, 8, Article 14395. https://doi.org/10.1038/ncomms14395

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

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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 ∼ 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.",

author = "Sachin Hajarnis and Ronak Lakhia and Matanel Yheskel and Darren Williams and Mehran Sorourian and Xueqing Liu and Karam Aboudehen and Shanrong Zhang and Kara Kersjes and Ryan Galasso and Jian Li and Vivek Kaimal and Steven Lockton and Scott Davis and Andrea Flaten and Johnson, {Joshua A.} and Holland, {William L.} and Kusminski, {Christine M.} and Scherer, {Philipp E.} and Harris, {Peter C.} and Marie Trudel and Wallace, {Darren P.} and Peter Igarashi and Lee, {Edmund C.} and Androsavich, {John R.} and Vishal Patel",

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AU - Hajarnis, Sachin

AU - Lakhia, Ronak

AU - Yheskel, Matanel

AU - Williams, Darren

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

AU - Flaten, Andrea

AU - Johnson, Joshua A.

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

PY - 2017/2/16

Y1 - 2017/2/16

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.

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

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