title: MicroRNAs regulate renal tubule maturation through modulation of Pkd1.
abstract: 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 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 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.
authors.affiliation: Department of Internal Medicine/Nephrology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, MC 8856, Dallas, TX 75390, USA. Vishald.patel@utsouthwestern.edu
authors.forename: Vishal
authors.initials: V
authors.lastname: Patel
authors.forename: Sachin
authors.initials: S
authors.lastname: Hajarnis
authors.forename: Darren
authors.initials: D
authors.lastname: Williams
authors.forename: Ryan
authors.initials: R
authors.lastname: Hunter
authors.forename: Donovan
authors.initials: D
authors.lastname: Huynh
authors.forename: Peter
authors.initials: P
authors.lastname: Igarashi
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D053487:DEAD-box RNA Helicases / Q000235:genetics; D018628:Gene Dosage; D006801:Humans; D007684:Kidney Tubules / Q000254:growth & development*; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism*; D007690:Polycystic Kidney Diseases / Q000209:etiology; D043244:Ribonuclease III / Q000235:genetics; D050396:TRPP Cation Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D053487:DEAD-box RNA Helicases; D035683:MicroRNAs; D043244:Ribonuclease III; D050396:TRPP Cation Channels; C509781:Dicer1 protein, mouse