Basic Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Nephrol. Sep 7, 2018; 7(5): 108-116
Published online Sep 7, 2018. doi: 10.5527/wjn.v7.i5.108
Unique interstitial miRNA signature drives fibrosis in a murine model of autosomal dominant polycystic kidney disease
Ameya Patil, William E Sweeney Jr, Cynthia G Pan, Ellis D Avner
Ameya Patil, William E Sweeney Jr, Cynthia G Pan, Ellis D Avner, Children’s Research Institute; Children’s’ Hospital Health System of Wisconsin and the Medical College of Wisconsin, Milwaukee, WI 53226, United States
Author contributions: Patil A, Sweeney Jr WE, Pan CG and Avner ED all equally contributed to the conception and design of this study, analysis, and interpretation of data; all authors drafted the article and made critical revisions related to the intellectual content of the manuscript, and approved the final version of the article to be published.
Supported by the Children’s Research Institute, the Lillian Goldman Charitable Trust; Amy P Goldman Foundation; and Ellsworth Family and Children’s Foundation of Children’s’ Hospital and Health System of Wisconsin.
Institutional animal care and use committee statement: All animal experiments are conducted in accordance with policies of the NIH Guide for the Care and Use of Laboratory Animals and the Institutional Animal Care and Use Committee (IACUC) of the Medical College of Wisconsin. The IACUC at the Medical College of Wisconsin is properly appointed according to PHS policy IV.A.3.a and is qualified through the experience and expertise of its members to oversee the Institution’s animal care and use program. The Animal Welfare Assurance for the Medical College of Wisconsin is A3102-01. Specific protocols used in this study were approved by the Medical College of Wisconsin IACUC (approved protocols are AUA 4278 and AUA 4179).
Conflict-of-interest statement: The authors have no conflict of interest to declare. Conflict of Interest in Research statements is on file with the institution as per Medical College of Wisconsin policy #RS.GN.020.
Data sharing statement: Data sets and statistical methods are available upon request from the corresponding author
ARRIVE guidelines statement: The manuscript was revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Ameya P Patil, MD, Assistant Professor, Department of Pediatrics, Medical College of Wisconsin, Children’s Research Institute, Children’s’ Hospital Health System of Wisconsin, Children’s Corporate Center, Suite 510, Mailstop CCC C510, 999 North 92nd Street, Milwaukee, WI 53226, United States. appatil@mcw.edu
Telephone: +1-414-9555773 Fax: +1-414-3377105
Received: April 21, 2018
Peer-review started: April 21, 2018
First decision: May 16, 2018
Revised: May 25, 2018
Accepted: July 31, 2018
Article in press: August 1, 2018
Published online: September 7, 2018
Processing time: 139 Days and 13 Hours
ARTICLE HIGHLIGHTS
Research background

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic renal condition, with an incidence of 1 in 500 to 1000 individuals. ADPKD affects approximately 750,000 people in the United States and 12.5 million people worldwide. Nearly 50% of ADPKD patients will develop kidney failure that requires dialysis or transplantation. To date, clinical trials targeting cyst growth (epithelial proliferation) have been largely ineffective in improving or slowing the decline in renal function, despite reducing epithelial proliferation and total kidney volume (TKV). Tolvaptan, the most promising therapy to date, has an estimated cost of $744,100 per year per quality-adjusted life-year gained compared with standard care.

Research motivation

In ADPKD, as fluid-filled cysts develop and enlarge, a peri-cystic local micro-environment (PLM) is created between the cysts, which become fibrotic over time. TKV decreases with such fibrotic changes and has a strong correlation with loss of renal function. Despite this connection between fibrosis and end-stage renal disease (ESRD), there is no experimental or FDA-approved therapy that specifically targets fibrosis in ADPKD.

Research objectives

To investigate miRNA expression in PLM between cysts that become fibrotic as disease progresses.

Research methods

We employed LCM to analyze the miRNA profile of PLM at PN21, prior to any morphometric sign of fibrosis (trichrome stain), and at two time points of increasing degrees of fibrotic severity at PN28 (initiation) and PN42 (progression). These results were compared to age-matched expression profiles of whole kidney analysis of the miRNA expression profile.

Research results

The most striking result of these studies was the difference in miRNA profiles from PLM and whole kidney, as shown in cluster heat maps. The expression of miRNAs in the PLM was significantly distinct when compared to whole kidney expression.

Research conclusions

Relying on whole kidney analysis may lead one to pursue not only the wrong miRNA, but may also lead to targeting a miRNA or protein that exacerbates the disease process you are trying to ameliorate. Therefore, published data that relies upon whole kidney transcriptomic analysis should be viewed with careful skepticism. Identification of the molecular and cellular changes in the PLM will lead to new therapeutic targets, with the potential to prevent the initiation or slow the progression of fibrosis.

Research perspectives

This study presents a unique approach to identify novel molecular and therapeutic targets that initiate and drive interstitial fibrosis in ADPKD. The use of therapies targeting fibrosis alone or in combination with therapies targeting epithelial proliferation will dramatically improve the quality of life of ADPKD patients by extending the time to ESRD.