TY - JOUR
T1 - Anti-microRNA screen uncovers miR-17 family within miR-17~92 cluster as the primary driver of kidney cyst growth
AU - Yheskel, Matanel
AU - Lakhia, Ronak
AU - Cobo-Stark, Patricia
AU - Flaten, Andrea
AU - Patel, Vishal
N1 - Funding Information:
We thank the UT Southwestern O’Brien Kidney Research Core Center (P30DK079328), the Mayo Translation PKD center (DK090728), UT Southwestern Bioinformatics core, Dr. Thomas Carroll (UT Southwestern), and Dr. Beth Levine (UT Southwestern) for providing critical reagents and services. We thank Dr. Silvia Ferrè (UT Southwestern) for helpful comments and discussion during the preparation of this manuscript. The work from the authors’ laboratory is supported by National Institute of Health (R01DK102572) and the Department of Defense (D01 W81XWH1810673) to V.P. Vishal Patel have applied for a patent related to the treatment of polycystic kidney disease using miR-17 inhibitors. The Patel lab has a sponsored research agreement with Regulus Therapeutics. The remaining authors declare no conflict of interests.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41598-019-38566-y
DO - 10.1038/s41598-019-38566-y
M3 - Article
C2 - 30760828
AN - SCOPUS:85061478081
VL - 9
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 1920
ER -