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Published on: February 3, 2012
Ablation of Long Noncoding RNA Hoxb3os Exacerbates Cystogenesis in Mouse Polycystic Kidney Disease
Ivan Weisser1, Kara Eckberg1, Stephen D'Amico2
1Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
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; Pkd1F/F (rapid cyst progression) and Pkd1RC/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 Ser 473 , 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.
Insights
This study reveals that the long noncoding RNA Hoxb3os is downregulated in autosomal dominant polycystic kidney disease (ADPKD). Its absence worsens kidney cyst growth by activating mTORC2 signaling, suggesting lncRNAs as potential therapeutic targets for PKD.
Area of Science:
- Molecular Biology
- Genetics
- Biochemistry
Background:
- Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder causing kidney cysts, primarily due to mutations in PKD1 or PKD2.
- Long noncoding RNAs (lncRNAs) are increasingly recognized for their roles in disease, yet their involvement in ADPKD remains largely unexplored.
Purpose of the Study:
- To investigate the role of the lncRNA Hoxb3os in the pathogenesis of ADPKD.
- To determine if Hoxb3os influences the mammalian target of rapamycin (mTOR)/Akt signaling pathway in the context of kidney disease.
Main Methods:
- Ablation of Hoxb3os expression in mouse models of polycystic kidney disease (PKD).
- Analysis of mTOR/Akt signaling pathway components, including Rictor and phosphorylated Akt.
- Assessment of kidney cell proliferation and cyst development in genetically modified mice.
Main Results:
- Hoxb3os-null mice exhibited activated mTOR/Akt signaling and increased kidney cell proliferation.
- Ablation of Hoxb3os significantly exacerbated cyst growth and number in two different Pkd1 mouse models.
- Double-knockout mice (Pkd1 and Hoxb3os) showed enhanced mTORC2 signaling, indicated by increased Rictor and phosphorylated Akt levels.
Conclusions:
- Downregulation of Hoxb3os in ADPKD contributes to cystogenesis by dysregulating mTORC2 signaling.
- Targeting lncRNAs like Hoxb3os presents a potential therapeutic strategy for PKD.
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