MiR-17~92 miRNA cluster promotes kidney cyst growth in polycystic kidney disease

Vishal Patel, Darren Williams, Sachin Hajarnis, Ryan Hunter, Marco Pontoglio, Stefan Somlo, Peter Igarashi

Research output: Contribution to journalArticlepeer-review

98 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)10765-10770
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number26
DOIs
StatePublished - Jun 25 2013

Keywords

  • Autosomal dominant polycystic kidney disease
  • Cilia
  • Kinesin family member 3A

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'MiR-17~92 miRNA cluster promotes kidney cyst growth in polycystic kidney disease'. Together they form a unique fingerprint.

Cite this