Anti-microRNA screen uncovers miR-17 family within miR-17~92 cluster as the primary driver of kidney cyst growth
| Autor: | Matanel Yheskel, Andrea Flaten, Ronak Lakhia, Vishal Patel, Patricia Cobo-Stark |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Autosomal dominant polycystic kidney disease lcsh:Medicine Biology Kidney cysts Article Mice 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Gene expression microRNA medicine Animals Cyst lcsh:Science PI3K/AKT/mTOR pathway Mice Knockout Regulation of gene expression Multidisciplinary lcsh:R Polycystic Kidney Autosomal Dominant medicine.disease MicroRNAs 030104 developmental biology Gene Expression Regulation Multigene Family Cancer research lcsh:Q medicine.symptom 030217 neurology & neurosurgery |
| Zdroj: | Scientific Reports Scientific Reports, Vol 9, Iss 1, Pp 1-11 (2019) |
| ISSN: | 2045-2322 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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