Abstract：
:Selective pericyte loss, the histological hallmark of early diabetic retinopathy (DR), enhances the breakdown of the blood-retinal barrier (BRB) in diabetes. However, the role of pericytes on BRB alteration in diabetes and the signaling pathways involved in their effects are currently unknown. To understand the role of diabetes-induced molecular alteration of pericytes, we performed transcriptomic analysis of sorted retinal pericytes from mice model of diabetes. Retinal tissue from non-diabetic and diabetic (duration 3 months) mouse eyes (n = 10 in each group) were used to isolate pericytes through fluorescent activated cell sorting (FACS) using pericyte specific fluorescent antibodies, PDGFRb-APC. For RNA sequencing and qPCR analysis, a cDNA library was generated using template switching oligo and the resulting libraries were sequenced using paired-end Illumina sequencing. Molecular functional pathways were analyzed using differentially expressed genes (DEGs). Differential expression analysis revealed 217 genes significantly upregulated and 495 genes downregulated, in pericytes isolated from diabetic animals. These analyses revealed a core set of differentially expressed genes that could potentially contribute to the pericyte dysfunction in diabetes and highlighted the pattern of functional connectivity between key candidate genes and blood retinal barrier alteration mechanisms. The top up-regulated gene list included: Ext2, B3gat3, Gpc6, Pip5k1c and Pten and down-regulated genes included: Notch3, Xbp1, Gpc4, Atp1a2 and AKT3. Out of these genes, we further validated one of the down regulated genes, Notch 3 and its role in BRB alteration in diabetic retinopathy. We confirmed the downregulation of Notch3 expression in human retinal pericytes exposed to Advanced Glycation End-products (AGEs) treatment mimicking the chronic hyperglycemia effect. Exploration of pericyte-conditioned media demonstrated that loss of NOTCH3 in pericyte led to increased permeability of endothelial cell monolayers. Collectively, we identify a role for NOTCH3 in pericyte dysfunction in diabetes. Further validation of other DEGs to identify cell specific molecular change through whole transcriptomic approach in diabetic retina will provide novel insight into the pathogenesis of DR and novel therapeutic targets.
journal_name
Exp Eye Resjournal_title
Experimental eye researchauthors
Rangasamy S,Monickaraj F,Legendre C,Cabrera AP,Llaci L,Bilagody C,McGuire P,Das Adoi
10.1016/j.exer.2020.108043subject
Has Abstractpub_date
2020-06-01 00:00:00pages
108043eissn
0014-4835issn
1096-0007pii
S0014-4835(20)30302-Xjournal_volume
195pub_type
杂志文章abstract：:The eye lens is a transparent and avascular organ in the front of the eye that is responsible for focusing light onto the retina in order to transmit a clear image. A monolayer of epithelial cells covers the anterior hemisphere of the lens, and the bulk of the lens is made up of elongated and differentiated fiber cell...
journal_title：Experimental eye research
pub_type： 杂志文章,评审
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journal_title：Experimental eye research
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journal_title：Experimental eye research
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journal_title：Experimental eye research
pub_type： 杂志文章
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journal_title：Experimental eye research
pub_type： 杂志文章
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journal_title：Experimental eye research
pub_type： 杂志文章
doi：10.1006/exer.1994.1003
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journal_title：Experimental eye research
pub_type： 杂志文章
doi：10.1016/j.exer.2004.10.006
更新日期：2005-03-01 00:00:00
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pub_type： 杂志文章
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journal_title：Experimental eye research
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journal_title：Experimental eye research
pub_type： 杂志文章
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更新日期：1993-08-01 00:00:00
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pub_type： 杂志文章
doi：10.1016/j.exer.2013.05.013
更新日期：2013-08-01 00:00:00
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journal_title：Experimental eye research
pub_type： 杂志文章
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更新日期：1985-09-01 00:00:00
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journal_title：Experimental eye research
pub_type： 杂志文章
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更新日期：1991-10-01 00:00:00
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journal_title：Experimental eye research
pub_type： 杂志文章
doi：10.1006/exer.1993.1158
更新日期：1993-11-01 00:00:00
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pub_type： 杂志文章
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更新日期：2016-04-01 00:00:00
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更新日期：2019-05-01 00:00:00
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pub_type： 杂志文章
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更新日期：1990-02-01 00:00:00
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journal_title：Experimental eye research
pub_type： 杂志文章,评审
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journal_title：Experimental eye research
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journal_title：Experimental eye research
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journal_title：Experimental eye research
pub_type： 杂志文章
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journal_title：Experimental eye research
pub_type： 杂志文章
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更新日期：2015-07-01 00:00:00
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journal_title：Experimental eye research
pub_type： 杂志文章
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