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MicroRNAs (miRNAs) play an important role in regulating gene expression in health and disease but their role in modifying disease expression in Autosomal Dominant Polycystic Kidney Disease (ADPKD) remains uncertain. Here, we profiled human urinary exosome miRNA by global small RNA-sequencing in an initial discovery cohort of seven patients with ADPKD with early disease (eGFR over 60ml/min/1.73m 2 ), nine with late disease (eGFR under 60ml/min/1.73m 2 ), and compared their differential expression with six age and sex matched healthy controls. Two kidney-enriched candidate miRNA families were identified (miR-192/miR-194-2 and miR-30) and selected for confirmatory testing in a 60 patient validation cohort by quantitative polymerase chain reaction. We confirmed that miR-192-5p, miR-194-5p, miR-30a-5p, miR-30d-5p and miR-30e-5p were significantly downregulated in patient urine exosomes, in murine Pkd1 cystic kidneys and in human PKD1 cystic kidney tissue. All five miRNAs showed significant correlations with baseline eGFR and ultrasound-determined mean kidney length and improved the diagnostic performance (area under the curve) of mean kidney length for the rate of disease progression. Finally, inverse correlations of these two miRNA families with increased expression in their predicted target genes in patient PKD1 cystic tissue identified dysregulated pathways and transcriptional networks including novel interactions between miR-194-5p and two potentially relevant candidate genes, PIK3R1 and ANO1. Thus, our results identify a subset of urinary exosomal miRNAs that could serve as novel biomarkers of disease progression and suggest new therapeutic targets in ADPKD., (Copyright © 2020 International Society of Nephrology. All rights reserved.)

Autosomal dominant polycystic kidney disease (ADPKD) is the fourth most common cause of end-stage renal disease. The disease course can be highly variable and treatment options are limited. To identify new therapeutic targets and prognostic biomarkers of disease, we conducted parallel discovery microarray profiling in normal and diseased human PKD1 cystic kidney cells. A total of 1,515 genes and 5 miRNA were differentially expressed by more than twofold in PKD1 cells. Functional enrichment analysis identified 30 dysregulated signaling pathways including the epidermal growth factor (EGF) receptor pathway. In this paper, we report that the EGF/ErbB family receptor ErbB4 is a major factor driving cyst growth in ADPKD. Expression of ErbB4 in vivo was increased in human ADPKD and Pkd1 cystic kidneys, both transcriptionally and posttranscriptionally by mir-193b-3p. Ligand-induced activation of ErbB4 drives cystic proliferation and expansion suggesting a pathogenic role in cystogenesis. Our results implicate ErbB4 activation as functionally relevant in ADPKD, both as a marker of disease activity and as a new therapeutic target in this major kidney disease., (Copyright © 2017 the American Physiological Society.)