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Abstract: FR-PO733

Global MicroRNA Profiling in Human Urinary Exosomes Reveals Novel Disease Biomarkers and Cellular Pathways for ADPKD

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic

Authors

  • Streets, Andrew J., University of Sheffield, Sheffield, United Kingdom
  • Magayr, Tajdida Abokhzam, University of Sheffield, Sheffield, United Kingdom
  • Vergoz, Laura, University of Sheffield, Sheffield, United Kingdom
  • Ong, Albert C., University of Sheffield, Sheffield, United Kingdom

Group or Team Name

  • Kidney Genetics Group
Background

ADPKD is the most common genetic kidney disease and the fourth most common cause of end-stage renal disease (ESRD) world-wide. Although PKD1 and PKD2 patients present different phenotypes, a high intra-familial variability in disease progression has been observed, suggesting that other genetic or environmental factors have major influences on progression of ADPKD.

Methods

Spot urine specimens were collected from patients with ADPKD and healthy controls. Global miRNA-sequencing was conducted in urine exosome-derived miRNAs from healthy volunteers, ADPKD patients with early (eGFR > 60 mL/min) or late (eGFR < 60 mL/min) disease in a discovery cohort (n=22). TaqMan qPCR was carried out in a clinically phenotyped validation cohort (n=60) and in a Pkd1 mouse model. In silico bioinformatic analyses identified altered miRNA target genes and disease pathways.

Results

Discovery phase RNA-seq identified a number of dysregulated miRNAs in ADPKD derived exosomes. Two candidate miRNA families identified (miR-192/miR-194-2 and miR-30) were selected for testing by qPCR in a validation cohort (n=60) and in an established mouse Pkd1 model. We confirmed that miR-192-5p, miR-194-5p, miR-30a-5p, miR-30d-5p and miR-30e-5p were significantly downregulated in human urine exosomes and in Pkd1 cystic kidneys. Expression levels of all five miRNAs showed significant correlations with baseline eGFR-EPI and ultrasound-mean kidney length (MKL) and improved the diagnostic performance (AUC) of MKL for the rate of disease progression. Finally, by analysing inverse correlations of these two miRNA families with the increased expression of their predicted target genes, we identified several dysregulated pathways and transcriptional networks. These included novel miR-194-5p interactions with the 3’UTR of ANO1 and PIK3R1. Inhibition of these two candidate genes in human PKD1 cystic cells significantly reduced cyst growth in vitro, confirming their functional significance.

Conclusion

Our results demonstrate that urine exosome global miRNA profiling can be a powerful tool to identify ADPKD patients with rapid disease progression who could benefit from disease modifying treatment. We have identified a subset of urinary exosomal miRNAs that could serve as novel biomarkers of disease progression and also suggest potential new therapeutic targets in ADPKD.

Funding

  • Government Support - Non-U.S.