title: miR-17~92 miRNA cluster promotes kidney cyst growth in polycystic kidney disease.
abstract: Polycystic kidney disease (PKD), the most common genetic cause of chronic kidney failure, is characterized by the presence of numerous, progressively enlarging fluid-filled cysts in the renal parenchyma. The cysts arise from renal tubules and are lined by abnormally functioning and hyperproliferative epithelial cells. Despite recent progress, no Food and Drug Administration-approved therapy is available to retard cyst growth. MicroRNAs (miRNAs) are short noncoding RNAs that inhibit posttranscriptional gene expression. Dysregulated miRNA expression is observed in PKD, but whether miRNAs are directly involved in kidney cyst formation and growth is not known. Here, we show that miR-17∼92, an oncogenic miRNA cluster, is up-regulated in mouse models of PKD. Kidney-specific transgenic overexpression of miR-17∼92 produces kidney cysts in mice. Conversely, kidney-specific inactivation of miR-17∼92 in a mouse model of PKD retards kidney cyst growth, improves renal function, and prolongs survival. miR-17∼92 may mediate these effects by promoting proliferation and through posttranscriptional repression of PKD genes Pkd1, Pkd2, and hepatocyte nuclear factor-1β. These studies demonstrate a pathogenic role of miRNAs in mouse models of PKD and identify miR-17∼92 as a therapeutic target in PKD. Our results also provide a unique hypothesis for disease progression in PKD involving miRNAs and regulation of PKD gene dosage.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. vishald.patel@utsouthwestern.edu
authors.forename: Vishal
authors.initials: V
authors.lastname: Patel
authors.forename: Darren
authors.initials: D
authors.lastname: Williams
authors.forename: Sachin
authors.initials: S
authors.lastname: Hajarnis
authors.forename: Ryan
authors.initials: R
authors.lastname: Hunter
authors.forename: Marco
authors.initials: M
authors.lastname: Pontoglio
authors.forename: Stefan
authors.initials: S
authors.lastname: Somlo
authors.forename: Peter
authors.initials: P
authors.lastname: Igarashi
mesh_terms: D000818:Animals; D001483:Base Sequence; D049109:Cell Proliferation; D004195:Disease Models, Animal; D018450:Disease Progression; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D050396:TRPP Cation Channels / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
chemical_list: D035683:MicroRNAs; D050396:TRPP Cation Channels; C575895:MIRN17-92 microRNA, mouse
keywords: autosomal dominant polycystic kidney disease; cilia; kinesin family member 3A