| First Author | Yheskel M | Year | 2019 |
| Journal | Sci Rep | Volume | 9 |
| Issue | 1 | Pages | 1920 |
| PubMed ID | 30760828 | Mgi Jnum | J:298004 |
| Mgi Id | MGI:6457149 | Doi | 10.1038/s41598-019-38566-y |
| Citation | Yheskel M, et al. (2019) Anti-microRNA screen uncovers miR-17 family within miR-17~92 cluster as the primary driver of kidney cyst growth. Sci Rep 9(1):1920 |
| abstractText | 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. |
