Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2020.197
Suppression of Foxo3-Gatm by miR-132-3p Accelerates Cyst Formation by Up-Regulating ROS in Autosomal Dominant Polycystic Kidney Disease
Seonju Choi, Do Yeon Kim, Yejin Ahn, Eun Ji Lee and Jong Hoon Park*
Department of Biological Sciences and Research Institute of Women’s Health, Sookmyung Women’s University, Seoul 04310, Republic of Korea
*E-mail: parkjh@sookmyung.ac.kr
Tel: +82-2-710-9414, Fax: +82-2-2077-7258
The first three authors contributed equally to this work
Received: November 3, 2020; Revised: November 24, 2020; Accepted: November 25, 2020; Published online: January 7, 2021.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Accumulation of reactive oxygen species (ROS) is associated with the development of various diseases. However, the molecular mechanisms underlying oxidative stress that lead to such diseases like autosomal dominant polycystic kidney disease (ADPKD) remain unclear. Here, we observed that oxidative stress markers were increased in Pkd1f/f:HoxB7-Cre mice. Forkhead transcription factors of the O class (FOXOs) are known key regulators of the oxidative stress response, which have been observed with the expression of FoxO3a in an ADPKD mouse model in the present study. An integrated analysis of two datasets for differentially expressed miRNA, such as miRNA sequencing analysis of Pkd1 conditional knockout mice and microarray analysis of samples from ADPKD patients, showed that miR-132-3p was a key regulator of FOXO3a in ADPKD. miR-132-3p was significantly upregulated in ADPKD which directly targeted FOXO3 in both mouse and human cell lines. Interestingly, the mitochondrial gene Gatm was downregulated in ADPKD which led to a decreased inhibition of FOXO3. Overexpression of miR-132-3p coupled with knockdown of FOXO3 and Gatm increased ROS and accelerated cyst formation in 3D culture. This study reveals a novel mechanism involving miR-132-3p, FOXO3, and Gatm that is associated with the oxidative stress that occurs during cystogenesis in ADPKD.
Keywords: ADPKD, FOXO3, ROS, MicroRNA, Cystogenesis


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