Journal
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
Volume 23, Issue 12, Pages 1941-1948Publisher
AMER SOC NEPHROLOGY
DOI: 10.1681/ASN.2012030321
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Funding
- National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases [KO8 DK084311-01, 5RC1DK086887-02]
- University of Texas Southwestern O'Brien Kidney Research Core Center [NIH P30DK079328]
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MicroRNAs (miRNAs) contribute to the regulation of early kidney development, but their role during later stages of renal tubule maturation is not well understood. Here, we found that ablation of the miRNA-processing enzyme Dicer from maturing renal tubules produces tubular and glomerular cysts in mice. Inactivation of Dicer is associated with downregulation of miR-200, a kidney-enriched miRNA family, and up-regulation of the polycystic kidney disease gene Pkd1. Inhibition of miR-200 in cultured renal epithelial cells disrupted tubulogenesis and led to upregulation of Pkd1. Using bioinformatic and in vitro approaches, we found that miR-200b/c/429 induce post-transcriptional repression of Pkd1 through two conserved binding sites in the 3'-Untranslated regions of Pkd1. Overexpression of PKD1 in renal epithelial cells was sufficient to disrupt tubulogenesis and produce cyst-like structures. In conclusion, miRNAs are essential for the maturation of renal tubules, and Pkd1 is a target of miR-200. These results also suggest that miRNAs may modulate PKD1 gene dosage and play a role in the initiation of cystogenesis.
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