TY - JOUR
T1 - MicroRNAs regulate renal tubule maturation through modulation of Pkd1
AU - Patel, Vishal
AU - Hajarnis, Sachin
AU - Williams, Darren
AU - Hunter, Ryan
AU - Huynh, Donovan
AU - Igarashi, Peter
PY - 2012
Y1 - 2012
N2 - MicroRNAs (miRNAs) contribute to the regulation of early kidney development, but their role during later stages of renal tubulematuration 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 upregulation 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 39-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.
AB - MicroRNAs (miRNAs) contribute to the regulation of early kidney development, but their role during later stages of renal tubulematuration 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 upregulation 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 39-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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U2 - 10.1681/ASN.2012030321
DO - 10.1681/ASN.2012030321
M3 - Article
C2 - 23138483
AN - SCOPUS:84870533401
SN - 1046-6673
VL - 23
SP - 1941
EP - 1948
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 12
ER -