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.
| Original language | English (US) |
|---|---|
| Article number | 1920 |
| Journal | Scientific Reports |
| Volume | 9 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 1 2019 |
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ASJC Scopus subject areas
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Cite this
Anti-microRNA screen uncovers miR-17 family within miR-17~92 cluster as the primary driver of kidney cyst growth. / Yheskel, Matanel; Lakhia, Ronak K; Cobo-Stark, Patricia; Flaten, Andrea; Patel, Vishal D.
In: Scientific Reports, Vol. 9, No. 1, 1920, 01.12.2019.Research output: Contribution to journal › Article
}
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 K
AU - Cobo-Stark, Patricia
AU - Flaten, Andrea
AU - Patel, Vishal D
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.
UR - http://www.scopus.com/inward/record.url?scp=85061478081&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85061478081&partnerID=8YFLogxK
U2 - 10.1038/s41598-019-38566-y
DO - 10.1038/s41598-019-38566-y
M3 - Article
VL - 9
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 1920
ER -