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Describing a Transcription Factor Dependent Regulation of the MicroRNA Transcriptome
Published on: June 15, 2016
MicroRNA-24 protects retina from degeneration in rats by down-regulating chitinase-3-like protein 1
Chunpin Lian1, Hui Lou2, Jingfa Zhang3
1Department of Ophthalmology of Shanghai Tenth People's Hospital, Tongji Eye Institute, Tongji University School of Medicine, Shanghai, 200092, China; Laboratory of Clinical Visual Science, Department of Regenerative Medicine, and Stem Cell Research Center, and Department of Pharmacology, Tongji University School of Medicine, Shanghai, 200092, China.
Abstract:
MicroRNAs (miRNAs) have been shown to play critical roles in the pathogenesis and progression of degenerative retinal diseases like age-related macular degeneration (AMD). In this study, we first demonstrated that miR-24 plays an important role in maintaining retinal structure and visual function of rats by targeting chitinase-3-like protein 1 (CHI3L1). In the retinal pigment epithelial (RPE) cells of Royal College of Surgeons (RCS) rats, an animal model of genetic retinal degeneration (RD), miR-24 was found lower and CHI3L1 level was higher in comparison with those in Sprague-Dawley (SD) rats. Other changes in the eyes of RCS rats include activated AKT/mTOR and ERK pathways and abnormal autophagy in the RPE cells. Such roles of miR-24 and CHI3L1 were further confirmed in RCS rats by subretinal injection of agomiR-24, which decreased CHI3L1 level and preserved retinal structure and function. Upstream, NF-κB was identified as the regulator of miR-24 in the RPE cells of these rats. On the other hand, in SD rats, intraocular treatment of antagomiR-24 induced pathological changes similar to those in RCS rats. The results revealed the protective roles for miR-24 to RPE cells and a mechanism for RD in RCS rats was proposed: extracellular stress stimuli first activate the NF-κB signaling pathway, which lowers miR-24 expression so that CHI3L1 increased. CHI3L1 sequentially results in aberrant autophagy and RPE dysfunction by activating AKT/mTOR and ERK pathways. Taken together, although the possibility, that the therapeutic effects in RCS rats are caused by other transcriptional changes regulated by miR-24, cannot be excluded, these findings indicate that miR-24 protects rat retina by targeting CHI3L1. Thus, miR-24 and CHI3L1 might be the targets for developing more effective therapy for degenerative retinal diseases like AMD.
Insights
MicroRNA-24 (miR-24) protects retinal structure and function by targeting CHI3L1, offering a potential therapeutic target for degenerative retinal diseases like age-related macular degeneration (AMD).
Area of Science:
- Ophthalmology
- Molecular Biology
- Genetics
Background:
- Degenerative retinal diseases, such as age-related macular degeneration (AMD), involve complex molecular pathways affecting retinal pigment epithelial (RPE) cells.
- MicroRNAs (miRNAs) are implicated in the pathogenesis of these diseases, but specific roles and therapeutic targets remain under investigation.
- Chitinase-3-like protein 1 (CHI3L1) has been associated with retinal pathologies, but its precise regulatory mechanisms and interactions with miRNAs are not fully elucidated.
Purpose of the Study:
- To investigate the role of microRNA-24 (miR-24) in maintaining retinal structure and visual function.
- To identify the molecular targets and regulatory pathways of miR-24 in the context of retinal degeneration.
- To explore the potential of miR-24 as a therapeutic target for degenerative retinal diseases.
Main Methods:
- Comparative analysis of miR-24 and CHI3L1 levels in RPE cells of Royal College of Surgeons (RCS) rats (a genetic retinal degeneration model) and Sprague-Dawley (SD) rats.
- Investigation of signaling pathways (AKT/mTOR, ERK) and autophagy in RPE cells of RCS rats.
- In vivo experiments involving subretinal injection of agomiR-24 in RCS rats and antagomiR-24 in SD rats to assess functional and structural effects.
Main Results:
- Lower miR-24 and higher CHI3L1 levels were observed in RCS rat RPE cells compared to SD rats, correlating with activated AKT/mTOR, ERK pathways, and abnormal autophagy.
- Subretinal injection of agomiR-24 in RCS rats decreased CHI3L1, preserved retinal structure, and improved visual function.
- Intraocular treatment with antagomiR-24 in SD rats induced pathological changes mimicking those in RCS rats, and NF-κB was identified as an upstream regulator of miR-24.
Conclusions:
- miR-24 plays a protective role in RPE cells, maintaining retinal structure and function by targeting CHI3L1.
- A proposed mechanism involves NF-κB activation leading to reduced miR-24, increased CHI3L1, aberrant autophagy, and RPE dysfunction via AKT/mTOR and ERK pathways.
- miR-24 and CHI3L1 represent promising therapeutic targets for degenerative retinal diseases like age-related macular degeneration (AMD).
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