ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: TH-OR101

Anti-MicroRNA Screen Uncovers miR-17 Family within miR-17~92 Cluster as the Primary Driver of Kidney Cyst Growth

Session Information

Category: Genetic Diseases of the Kidney

  • 1001 Genetic Diseases of the Kidney: Cystic

Authors

  • Yheskel, Matanel, University of Texas Southwestern Medical Center, Dallas, Texas, United States
  • Lakhia, Ronak, University of Texas Southwestern Medical Center, Dallas, Texas, United States
  • Patel, Vishal, University of Texas Southwestern Medical Center, Dallas, Texas, United States
Background

We have recently shown that inhibiting miR-17~92 is a potential novel therapeutic approach for autosomal dominant polycystic kidney disease (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. The relative pathogenic contribution of these miRNA families to ADPKD progression is unknown.

Methods

We performed an in vivo anti-miR screen to identify drug targets within the miR-17~92 miRNA cluster. Locked nucleic acid-modified anti-miRs (12 to 16 nucleotides) were used to selectively inhibit either the miR-17, miR-18, miR-19, or miR-25 family in an orthologous model of ADPKD. miRNAs belonging to one family harbor identical seed sequence but there are minor differences in flanking nucleotides. To simultaneously inhibit all members of one family, anti-miRs were designed to Watson-Crick base pair with the majority but not the entire length of cognate mature miRNA sequence. Mice were randomly assigned to receive either 20 mg/kg of anti-miR-17, anti-miR-18, anti-miR-19, or anti-miR-25 family inhibitors, or vehicle at postnatal days (P) 10-12 and 15, and were sacrificed at P18 to assess cyst burden.

Results

Q-PCR analysis showed that anti-miRs specifically inhibit the cognate miRNA family members without affecting the expression of unrelated miRNAs. 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. RNA-seq analysis showed that anti-miR-17 treatment recapitulated the gene expression pattern observed after miR-17~92 genetic deletion. Additional analysis revealed that anti-miR-17 treatment was associated with upregulation of mitochondrial metabolism, suppression of the mTOR pathway, induction of autophagy, and reduction of cyst-associated inflammation (M2-like macrophages).

Conclusion

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 pathogenic component and therapeutic target for ADPKD. This new information is vital because it guides the substantial on-going drug development efforts aimed at targeting the miR-17~92 cluster for the treatment of human ADPKD.

Funding

  • NIDDK Support