Reciprocal Regulation between lncRNA ANRIL and p15 in Steroid-Induced Glaucoma
Steroid-induced glaucoma (SIG) is the most common adverse steroid-related effect on the eyes. SIG patients can suffer from trabecular meshwork (TM) dysfunction, intraocular pressure (IOP) elevation, and irreversible vision loss. Previous studies have mainly focused on the role of extracellular matri...
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| Format: | Article |
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MDPI AG
2022-04-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/11/9/1468 |
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| author | Peixing Wan Siyu Huang Yanting Luo Caibin Deng Jiajian Zhou Erping Long Yehong Zhuo |
| author_facet | Peixing Wan Siyu Huang Yanting Luo Caibin Deng Jiajian Zhou Erping Long Yehong Zhuo |
| author_sort | Peixing Wan |
| collection | DOAJ |
| description | Steroid-induced glaucoma (SIG) is the most common adverse steroid-related effect on the eyes. SIG patients can suffer from trabecular meshwork (TM) dysfunction, intraocular pressure (IOP) elevation, and irreversible vision loss. Previous studies have mainly focused on the role of extracellular matrix turnover in TM dysfunction; however, whether the cellular effects of TM cells are involved in the pathogenesis of SIG remains unclear. Here, we found that the induction of cellular senescence was associated with TM dysfunction, causing SIG in cultured cells and mouse models. Especially, we established the transcriptome landscape in the TM tissue of SIG mice via microarray screening and identified ANRIL as the most differentially expressed long non-coding RNA, with a 5.4-fold change. The expression level of ANRIL was closely related to ocular manifestations (IOP elevation, cup/disc ratio, and retinal nerve fiber layer thickness). Furthermore, p15, the molecular target of ANRIL, was significantly upregulated in SIG and was correlated with ocular manifestations in an opposite direction to ANRIL. The reciprocal regulation between ANRIL and p15 was validated using luciferase reporter assay. Through depletion in cultured cells and a mouse model, ANRIL/p15 signaling was confirmed in cellular senescence via cyclin-dependent kinase activity and, subsequently, by phosphorylation of the retinoblastoma protein. ANRIL depletion imitated the SIG phenotype, most importantly IOP elevation. ANRIL depletion-induced IOP elevation in mice can be effectively suppressed by p15 depletion. Analyses of the single-cell atlas and transcriptome dynamics of human TM tissue showed that ANRIL/p15 expression is spatially enriched in human TM cells and is correlated with TM dysfunction. Moreover, ANRIL is colocalized with a GWAS risk variant (rs944800) of glaucoma, suggesting its potential role underlying genetic susceptibility of glaucoma. Together, our findings suggested that steroid treatment promoted cellular senescence, which caused TM dysfunction, IOP elevation, and irreversible vision loss. Molecular therapy targeting the ANRIL/p15 signal exerted a protective effect against steroid treatment and shed new light on glaucoma management. |
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| language | English |
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| spelling | doaj.art-25d245d7384c44ceb62725aa6c5a6e492023-11-23T07:59:38ZengMDPI AGCells2073-44092022-04-01119146810.3390/cells11091468Reciprocal Regulation between lncRNA ANRIL and p15 in Steroid-Induced GlaucomaPeixing Wan0Siyu Huang1Yanting Luo2Caibin Deng3Jiajian Zhou4Erping Long5Yehong Zhuo6State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, ChinaState Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, ChinaState Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, ChinaState Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, ChinaDermatology Hospital, Southern Medical University, Guangzhou 510091, ChinaState Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, ChinaState Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, ChinaSteroid-induced glaucoma (SIG) is the most common adverse steroid-related effect on the eyes. SIG patients can suffer from trabecular meshwork (TM) dysfunction, intraocular pressure (IOP) elevation, and irreversible vision loss. Previous studies have mainly focused on the role of extracellular matrix turnover in TM dysfunction; however, whether the cellular effects of TM cells are involved in the pathogenesis of SIG remains unclear. Here, we found that the induction of cellular senescence was associated with TM dysfunction, causing SIG in cultured cells and mouse models. Especially, we established the transcriptome landscape in the TM tissue of SIG mice via microarray screening and identified ANRIL as the most differentially expressed long non-coding RNA, with a 5.4-fold change. The expression level of ANRIL was closely related to ocular manifestations (IOP elevation, cup/disc ratio, and retinal nerve fiber layer thickness). Furthermore, p15, the molecular target of ANRIL, was significantly upregulated in SIG and was correlated with ocular manifestations in an opposite direction to ANRIL. The reciprocal regulation between ANRIL and p15 was validated using luciferase reporter assay. Through depletion in cultured cells and a mouse model, ANRIL/p15 signaling was confirmed in cellular senescence via cyclin-dependent kinase activity and, subsequently, by phosphorylation of the retinoblastoma protein. ANRIL depletion imitated the SIG phenotype, most importantly IOP elevation. ANRIL depletion-induced IOP elevation in mice can be effectively suppressed by p15 depletion. Analyses of the single-cell atlas and transcriptome dynamics of human TM tissue showed that ANRIL/p15 expression is spatially enriched in human TM cells and is correlated with TM dysfunction. Moreover, ANRIL is colocalized with a GWAS risk variant (rs944800) of glaucoma, suggesting its potential role underlying genetic susceptibility of glaucoma. Together, our findings suggested that steroid treatment promoted cellular senescence, which caused TM dysfunction, IOP elevation, and irreversible vision loss. Molecular therapy targeting the ANRIL/p15 signal exerted a protective effect against steroid treatment and shed new light on glaucoma management.https://www.mdpi.com/2073-4409/11/9/1468steroidcellular senescenceglaucomalncRNA |
| spellingShingle | Peixing Wan Siyu Huang Yanting Luo Caibin Deng Jiajian Zhou Erping Long Yehong Zhuo Reciprocal Regulation between lncRNA ANRIL and p15 in Steroid-Induced Glaucoma Cells steroid cellular senescence glaucoma lncRNA |
| title | Reciprocal Regulation between lncRNA ANRIL and p15 in Steroid-Induced Glaucoma |
| title_full | Reciprocal Regulation between lncRNA ANRIL and p15 in Steroid-Induced Glaucoma |
| title_fullStr | Reciprocal Regulation between lncRNA ANRIL and p15 in Steroid-Induced Glaucoma |
| title_full_unstemmed | Reciprocal Regulation between lncRNA ANRIL and p15 in Steroid-Induced Glaucoma |
| title_short | Reciprocal Regulation between lncRNA ANRIL and p15 in Steroid-Induced Glaucoma |
| title_sort | reciprocal regulation between lncrna anril and p15 in steroid induced glaucoma |
| topic | steroid cellular senescence glaucoma lncRNA |
| url | https://www.mdpi.com/2073-4409/11/9/1468 |
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