MicroRNA-21 aggravates cyst growth in a model of polycystic kidney disease

Ronak Lakhia, Sachin Hajarnis, Darren Williams, Karam Aboudehen, Matanel Yheskel, Chao Xing, Mark E. Hatley, Vicente E. Torres, Darren P. Wallace, Vishal Patel

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Autosomal dominant polycystic kidney disease (ADPKD), one of the most common monogenetic disorders, is characterized by kidney failure caused by bilateral renal cyst growth. MicroRNAs (miRs) have been implicated innumerous diseases, but the role of the senoncoding RNAs in ADPKD pathogenesis is still poorly defined. Here, we investigated the role of miR-21, an oncogenic miR, in kidney cyst growth. We found that transcriptional activation of miR-21 is a common feature of murine PKD. Furthermore, compared with renal tubules from kidney samples of normal controls, cysts in kidney samples from patients with ADPKD had increased levels of miR-21. cAMP signaling, a key pathogenic pathway in PKD, transactivated miR-21 promoter in kidney cells and promoted miR-21 expression in cystic kidneys of mice. Genetic deletion of miR-21 attenuated cyst burden, reduced kidney injury, and improved survival of an orthologous model of ADPKD. RNA sequencing analysis and additional in vivo assays showed that miR-21 inhibits apoptosis of cyst epithelial cells, likelythrough direct repressionofits target geneprogrammed cell death 4. Thus, miR-21 functions downstream of the cAMP pathway and promotes disease progression in experimental PKD. Our results suggest that inhibiting miR-21 is a potential new therapeutic approach to slow cyst growth in PKD.

Original languageEnglish (US)
Pages (from-to)2319-2330
Number of pages12
JournalJournal of the American Society of Nephrology
Volume27
Issue number8
DOIs
StatePublished - 2016

Bibliographical note

Funding Information:
We thank Peter Igarashi for guidance and support during the course of this project, Eric Olson for helping with planning the initial stages of this study and providing the miR-21 mice, and Stefan Somlo for providing Pkd1 and Pkd2 mice. We also thank Beverly Huet for statistical analysis. We thank the University of Texas Southwestern O'Brien Kidney Research Core Center, the Yale Center for Polycystic Kidney Disease Research, the McDermott Center Sequencing and Bioinformatics Core, and University of Texas Southwestern Metabolic Phenotyping Cores for providing critical reagents and services. R.L. is supported by Institutional National Institutes of Health Training Grant T32-DK007257. The Polycystic Kidney Disease Research Biomaterials and Cellular Models Core at the University of Kansas Medical Center is supported by a grant from the Polycystic Kidney Disease (PKD) Foundation (to D.P.W.). Work from the authors' laboratory is supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants R03DK099568-01 (to V.P.) and R01 DK102572 (to V.P.) and a grant from the PKD Foundation (to V.P.).

Publisher Copyright:
© Copyright 2016 by the American Society of Nephrology.

Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.

Fingerprint Dive into the research topics of 'MicroRNA-21 aggravates cyst growth in a model of polycystic kidney disease'. Together they form a unique fingerprint.

Cite this