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

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

doi:10.1038/ncomms14395

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.

Highlights

Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent genetic cause of renal failure
Using complementary genetic and pharmaceutical approaches, we show that miR-17B92 promotes cyst proliferation and ADPKD progression. miR-17 mediates these effects by reprogramming mitochondrial metabolism through direct repression of Ppara
Forty-five miRNAs were differentially expressed in Pkd1-KO kidney, whereas 70 miRNAs were differentially expressed in Pkd2-KO kidneys (Supplementary Table 1)

Summary

Introduction

Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent genetic cause of renal failure. Genetic deletion of the miR-17B92 cluster inhibits cyst proliferation and PKD progression in four orthologous, including two long-lived, mouse models of ADPKD. C-Myc upregulates miR-17B92 in cystic kidneys, which in turn aggravates cyst growth by inhibiting oxidative phosphorylation and stimulating proliferation through direct repression of Ppara. Anti-miRs appear to be well tolerated in human clinical trials[9], have a long duration of action and are efficiently delivered to the liver and kidney[10,11]. We found that among upregulated miRNAs, the miR-17 miRNA family contributed most substantially to the total dysregulated miRNA pool in both ADPKD models These unbiased microarray results and the previous observations in the Kif3a-KO mice prompted us to study the role of miR-17 in ADPKD. Using complementary genetic and pharmaceutical approaches, we show that miR-17B92 promotes cyst proliferation and ADPKD progression. miR-17 mediates these effects by reprogramming mitochondrial metabolism through direct repression of Ppara

Methods

Results

Conclusion