Anti-microRNA screen uncovers miR-17 family within miR-17~92 cluster as the primary driver of kidney cyst growth

Matanel Yheskel,Ronak Lakhia,Andrea Flaten,Vishal Patel,Patricia Cobo-Stark

doi:10.1038/s41598-019-38566-y

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is the leading genetic cause of renal failure. We have recently shown that inhibiting miR-17~92 is a potential novel therapeutic approach for ADPKD. However, miR-17~92 is a polycistronic cluster that encodes microRNAs (miRNAs) belonging to the miR-17, miR-18, miR-19 and miR-25 families, and the relative pathogenic contribution of these miRNA families to ADPKD progression is unknown. Here we performed an in vivo anti-miR screen to identify the miRNA drug targets within the miR-17~92 miRNA cluster. We designed anti-miRs to individually inhibit miR-17, miR-18, miR-19 or miR-25 families in an orthologous ADPKD model. Treatment with anti-miRs against the miR-17 family reduced cyst proliferation, kidney-weight-to-body-weight ratio and cyst index. In contrast, treatment with anti-miRs against the miR-18, 19, or 25 families did not affect cyst growth. Anti-miR-17 treatment recapitulated the gene expression pattern observed after miR-17~92 genetic deletion and was associated with upregulation of mitochondrial metabolism, suppression of the mTOR pathway, and inhibition of cyst-associated inflammation. Our results argue against functional cooperation between the various miR-17~92 cluster families in promoting cyst growth, and instead point to miR-17 family as the primary therapeutic target for ADPKD.

Highlights

Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations in either PKD1 or PKD2, is one of the most common monogenetic disorders and the leading genetic cause of end-stage renal disease (ESRD) in the United States[1,2,3]
Quantitative real-time PCR (Q-PCR) analysis revealed that five of the six mature miRNAs derived from the miR-17~92 cluster were upregulated in cystic kidneys compared to control kidneys (Fig. 1A). miR-17 and miR-18a were the most upregulated showing an increase in expression by 133.2% and 142.9%, respectively
Five out of six miRNAs belonging to the miR-17 family, one out of two miRNAs belonging the miR-18 family, both miRNAs belonging to the miR-19 family, and two of four miRNAs belonging to the miR-25 family were upregulated in cystic kidneys compared to control kidneys

Summary

Introduction

Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations in either PKD1 or PKD2, is one of the most common monogenetic disorders and the leading genetic cause of end-stage renal disease (ESRD) in the United States[1,2,3]. The second question is while anti-miR-17 treatment slows cyst growth caused due to Pkd[2] mutations whether it will have similar beneficial effects in the setting of Pkd[1] mutations is not known This is a critical issue considering that nearly 80% of ADPKD patients harbor PKD1 mutations. Whether anti-miRs targeting the miR-17~92 cluster affect these pathways is unknown To address these questions, we used anti-miRs to selectively inhibit the expression of each miRNA family in an orthologous Pkd1-KO model of ADPKD. Anti-miR-17 treatment provided the additional benefit of reducing mTOR signaling These data suggest that, within the miR-17~92 cluster, the miR-17 family is the primary therapeutic target for ADPKD

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