Extensive Sub-RPE Complement Deposition in a Nonhuman Primate Model of Early Stage Diabetic Retinopathy
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ABSTRACT:
PROVIDER: PRJNA673804 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12964439_1.fastq.gz | Fastqsanger.gz | |||
| SRR12964439_2.fastq.gz | Fastqsanger.gz | |||
| SRR12964440_1.fastq.gz | Fastqsanger.gz | |||
| SRR12964440_2.fastq.gz | Fastqsanger.gz | |||
| SRR12964441_1.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: This study aims to reveal retinal abnormities in a spontaneous diabetic nonhuman primate (NHP) model and explore the mechanism of featured injuries. Methods: Twenty-eight cynomolgus monkeys were identified to suffer from spontaneous Type 2 diabetes from a colony of more than eight hundred aged monkeys and twenty-six age-matched ones were used as controls. Their blood biochemistry profiles were determined and the retinal changes were examined by multimodal imaging, hematoxylin-eosin (H&E) staining and immunofluorescence. Retinal pigment epithelium (RPE) cells were isolated and determined by RNA-sequencing and computational analyses. Results: Diabetic monkeys were characterized by early vascular and neural damage in the retina and dyslipidemia. The typical acellular capillaries and pericyte ghost were found in the diabetic retina, which also exhibited reduced retinal nerve fiber layer (RNFL) thickness compared to the controls. Of note, distinct sub-RPE drusenoid lesions were extensively observed in these diabetic monkeys and complements deposition including C3 and C5b-9 were accumulated in these lesions. The RNA-seq data of RPE cells showed complement activation, AGE/RAGE activation and 18 inflammatory response at the setting of diabetes. Consistently, the plasma levels of C3 and C4 were also increased in the diabetic monkeys. Conclusions: The spontaneous Type 2 diabetic cynomolgus monkeys featured with early-stage retinopathy including not only typical vascular and neural damage, but also a distinct sub-RPE deposition. The complement activation and metabolic stress of RPE cells in response to hyperglycemia might contribute to the deposition, revealing an unrecognized role of RPE cells in the early-stage pathological process of diabetic retinopathy (DR).
2021-03-31 | GSE160617 | GEO
Project description:PurposeThis study aims to reveal retinal abnormities in a spontaneous diabetic nonhuman primate model and explore the mechanism of featured injuries.MethodsTwenty-eight cynomolgus monkeys were identified to suffer from spontaneous type 2 diabetes from a colony of more than eight-hundred aged monkeys, and twenty-six age-matched ones were chosen as controls. Their blood biochemistry profiles were determined and retinal changes were examined by multimodal imaging, hematoxylin and eosin staining, and immunofluorescence. Retinal pigment epithelium (RPE) cells were further investigated by RNA sequencing and computational analyses.ResultsThese diabetic monkeys were characterized by early retinal vascular and neural damage and dyslipidemia. The typical acellular capillaries and pericyte ghost were found in the diabetic retina, which also exhibited reduced retinal nerve fiber layer thickness compared to controls (all P < 0.05). Of note, distinct sub-RPE drusenoid lesions were extensively observed in these diabetic monkeys (46.43% vs. 7.69%), and complements including C3 and C5b-9 were deposited in these lesions. RNA-seq analysis revealed complement activation, AGE/RAGE activation and inflammatory response in diabetic RPE cells. Consistently, the plasma C3 and C4 were particularly increased in the diabetic monkeys with drusenoid lesions (P = 0.028 and 0.029).ConclusionsThe spontaneous type 2 diabetic monkeys featured with early-stage retinopathy including not only typical vascular and neural damage but also a distinct sub-RPE deposition. The complement activation of RPE cells in response to hyperglycemia might contribute to the deposition, revealing an unrecognized role of RPE cells in the early-stage pathological process of diabetic retinopathy.
| S-EPMC7991921 | biostudies-literature
Project description:This dataset represent supplemental data for publication submitted to Human Molecular Genetics in 2022. Briefly, Efemp1 R345W is a protein misfolding-prone mutation in humans causing Doyne honeycomb retinal dystrophy/Mallatia Leventinese (DHRD/ML), a disease sharing similar clinical pathology with age-related macular degeneration (AMD). Efemp1R345W/R345W knock-in mice (Efemp1ki/ki mice) develop deposits on the basal side of retinal pigment epithelial (RPE) cells, which is complement C3- dependent. We assessed alternative complement pathway component factor B (Cfb) in sub-RPE deposit formation in Efemp1ki/ki mice.
2023-03-11 | PXD035772 | Pride
Project description:In diabetic retinopathy (DR), hyperglycemia induces retinal pigment epithelium (RPE) cell senescence via downregulation of PDZK1. PDZK1 overexpression counteracts senescence by binding 14-3-3ε to modulate mTOR signaling, reducing oxidative stress and enhancing autophagy. Both genetic PDZK1 restoration and pharmacologic senolysis (Nutlin-3a) attenuate retinal senescence and ameliorate early DR pathology, establishing the PDZK1-14-3-3ε-mTOR axis as a therapeutic target
2025-08-12 | GSE304545 | GEO
Project description:In diabetic retinopathy (DR), hyperglycemia induces retinal pigment epithelium (RPE) cell senescence via downregulation of PDZK1. PDZK1 overexpression counteracts senescence by binding 14-3-3ε to modulate mTOR signaling, reducing oxidative stress and enhancing autophagy. Both genetic PDZK1 restoration and pharmacologic senolysis (Nutlin-3a) attenuate retinal senescence and ameliorate early DR pathology, establishing the PDZK1-14-3-3ε-mTOR axis as a therapeutic target
2025-08-11 | GSE304690 | GEO
Project description:Purpose: The complement system is closely linked to the pathogenesis of age-related macular degeneration (AMD). Several complement genes are expressed in retinal pigment epithelium (RPE), and complement proteins accumulate in drusen. Further, a common variant of complement factor H (CFH) confers increased risk of developing AMD. Because the mechanisms by which changes in the function of CFH influence development of AMD are unclear, we examined ocular complement expression as a consequence of age in control and CFH null mutant mice. Methods: Gene expression in neuroretinas and RPE/choroid from young and aged WT and Cfh-/- C57BL/6J mice was analysed by microarrays. Expression of a wide range of complement genes was compared to expression in splenocytes and in liver tissue by qRT-PCR. Results: An age-associated increased expression of complement, particularly C1q, C3 and Factor B, in the RPE/choroid coincided with increased expression of the negative regulators Cfh and Cd59a in the neuroretina. Young mice deficient in CFH expressed Cd59a similar to WT, but failed to upregulate Cd59a expression with age. Both hepatic and splenic expression of Cd59a increased with age regardless of Cfh genotype. Conclusions: While the connection between CFH deficiency and failure to up-regulate CD59a remains unknown, these results suggest that expression of CD59 is tissue-specific and that neuroretinal regulation depends on CFH. This could contribute to the visual functional deficits and morphological changes in the Cfh-/- mouse retina that occur with age, and further suggests that deficient neuroretinal regulation of complement could represent an early event in AMD. Gene expression in neuroretinas and RPE/choroid from young and aged WT and Cfh-/- mice, 4 biological replicates in each group.
2012-10-02 | E-GEOD-38671 | biostudies-arrayexpress
Project description:In this study we examined the effect of T cell-derived cytokines on retinal pigment epithelial (RPE) cells with respect to expression of complement components. We used an in vitro co-culture system in which CD3/CD28-activated human T cells were separated from the human RPE cell line (ARPE-19) by a membrane. Differential gene expression in the RPE cells of complement factor genes was identified using gene arrays, and selected gene transcripts were validated by q-RT-PCR. Protein expression was determined by ELISA and immunoblotting. Co-culture with activated T cells increased RPE mRNA and/or protein expression of complement components C3, factors B, H, H-like 1, CD46, CD55, CD59, and clusterin, in a dose-dependent manner. Soluble factors derived from activated T cells are capable of increasing expression of complement components in RPE cells. This is important for the further understanding of inflammatory ocular diseases such as uveitis and age-related macular degeneration.
2011-02-02 | GSE17938 | GEO
Project description:Purpose: The complement system is closely linked to the pathogenesis of age-related macular degeneration (AMD). Several complement genes are expressed in retinal pigment epithelium (RPE), and complement proteins accumulate in drusen. Further, a common variant of complement factor H (CFH) confers increased risk of developing AMD. Because the mechanisms by which changes in the function of CFH influence development of AMD are unclear, we examined ocular complement expression as a consequence of age in control and CFH null mutant mice. Methods: Gene expression in neuroretinas and RPE/choroid from young and aged WT and Cfh-/- C57BL/6J mice was analysed by microarrays. Expression of a wide range of complement genes was compared to expression in splenocytes and in liver tissue by qRT-PCR. Results: An age-associated increased expression of complement, particularly C1q, C3 and Factor B, in the RPE/choroid coincided with increased expression of the negative regulators Cfh and Cd59a in the neuroretina. Young mice deficient in CFH expressed Cd59a similar to WT, but failed to upregulate Cd59a expression with age. Both hepatic and splenic expression of Cd59a increased with age regardless of Cfh genotype. Conclusions: While the connection between CFH deficiency and failure to up-regulate CD59a remains unknown, these results suggest that expression of CD59 is tissue-specific and that neuroretinal regulation depends on CFH. This could contribute to the visual functional deficits and morphological changes in the Cfh-/- mouse retina that occur with age, and further suggests that deficient neuroretinal regulation of complement could represent an early event in AMD.
2012-10-02 | GSE38671 | GEO
Project description:Retinal Pigment Epithelial (RPE) cells are located behind the retina and are critical for photoreceptor survival. Loss of RPE is associated with several pathogenic conditions such as Age Related Macular Degeneration and Retinitis Pigmentosa. RPE derived from human embryonic stem cells (hESC) offer a potential source for producing these cells for therapy. Here we report the molecular and cellular characterization of RPE differentiated from hESC. hESC derived RPE are capable of proliferation and lose their epithelial characteristics before becoming confluent and re-differentiating back into their typical pigmented, cobblestoned appearance. During the proliferative phase, they adopt a mesenchymal morphology and express mesenchymal markers. Our results demonstrate that this apparent Epithelial-Mesenchymal Transition is not regulated by the classical EMT transcription factors SNAIL and SLUG. Furthermore, it is possible to regulate RPE de-differentiation and re-differentiation by modulating the Wnt and BMP pathway respectively. These findings further our understanding of the genesis and expansion of RPE which is essential for their therapeutic use.
2013-01-17 | E-MTAB-960 | biostudies-arrayexpress
Project description:Dysfunction of the retinal pigmented epithelium (RPE) results in degeneration of photoreceptors and vision loss and is correlated with common blinding disorders in humans. Although many protein-coding genes are known to be expressed in RPEs and important for their development and maintenance, virtually nothing is known about the in vivo roles of non-protein coding transcripts in RPEs. The expression patterns of microRNAs (miRNAs) have been analyzed in a variety of ocular tissues, and few were implicated to play role in RPE based on studies in cell lines. Herein, through RPE specific conditional mutagenesis of Dicer1 or DGCR8, the importance of miRNA for RPE differentiation was uncovered. Interestingly, miRNAs were found to be dispensable for maintaining the RPE fate and survival, and yet they are essential for acquisition of important RPE properties such as the expression of genes involved in the visual cycle pathway, pigmentation and cell adhesion. Importantly miRNAs of the RPE were found to be required for maturation of the adjacent photoreceptors, specifically for the morphogenesis of the outer segments. The profiles of miRNA and mRNA altered in the Dicer1 deficient RPE point to a key role of miR-204 in regulation of RPE differentiation program in vivo and uncovers the importance of additional novel RPE miRNAs. The study exposes the combined regulatory activity of miRNAs of the RPE, which is required for RPE differentiation and for the development of the adjacent neuroretina. Effect of Dicer 1 deficiency on RPE miRNA and mRNA.
2015-06-16 | E-GEOD-69881 | biostudies-arrayexpress