Ablation of Long Noncoding RNA Hoxb3os Exacerbates Cystogenesis in Mouse Polycystic Kidney Disease

Author:

Weisser Ivan1,Eckberg Kara1ORCID,D'Amico Stephen2,Buttram Daniel1,Aboudehen Karam2ORCID

Affiliation:

1. Department of Medicine, University of Minnesota, Minneapolis, Minnesota

2. Department of Medicine, Stony Brook University, Stony Brook, New York

Abstract

Significance Statement Long noncoding RNAs (lncRNAs) are a class of nonprotein coding RNAs with pivotal functions in development and disease. They have emerged as an exciting new drug target category for many common conditions. However, the role of lncRNAs in autosomal dominant polycystic kidney disease (ADPKD) has been understudied. This study provides evidence implicating a lncRNA in the pathogenesis of ADPKD. We report that Hoxb3os is downregulated in ADPKD and regulates mammalian target of rapamycin (mTOR)/Akt pathway in the in vivo mouse kidney. Ablating the expression of Hoxb3os in mouse polycystic kidney disease (PKD) activated mTOR complex 2 (mTORC2) signaling and exacerbated the cystic phenotype. The results from our study provide genetic proof of concept for future studies that focus on targeting lncRNAs as a treatment option in PKD. Background ADPKD is a monogenic disorder characterized by the formation of kidney cysts and is primarily caused by mutations in two genes, PKD1 and PKD2. Methods In this study, we investigated the role of lncRNA Hoxb3os in ADPKD by ablating its expression in the mouse. Results Hoxb3os-null mice were viable and had grossly normal kidney morphology but displayed activation of mTOR/Akt signaling and subsequent increase in kidney cell proliferation. To determine the role of Hoxb3os in cystogenesis, we crossed the Hoxb3os-null mouse to two orthologous Pkd1 mouse models: Pkhd1/Cre; Pkd1 F/F (rapid cyst progression) and Pkd1 RC/RC (slow cyst progression). Ablation of Hoxb3os exacerbated cyst growth in both models. To gain insight into the mechanism whereby Hoxb3os inhibition promotes cystogenesis, we performed western blot analysis of mTOR/Akt pathway between Pkd1 single-knockout and Pkd1-Hoxb3os double-knockout (DKO) mice. Compared with single-knockout, DKO mice presented with enhanced levels of total and phosphorylated Rictor. This was accompanied by increased phosphorylation of Akt at Ser473, a known mTORC2 effector site. Physiologically, kidneys from DKO mice displayed between 50% and 60% increase in cell proliferation and cyst number. Conclusions The results from this study indicate that ablation of Hoxb3os in mouse PKD exacerbates cystogenesis and dysregulates mTORC2.

Funder

National Institute of Diabetes and Digestive and Kidney Diseases

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Nephrology,General Medicine

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3