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Identification of key regulatory pathways in response to long-term zinc supplementation in human primary retinal pigment epithelium: a multi-omics approachIdentification of key regulatory pathways in response to long-term zinc supplementation in human primary retinal pigment epithelium: a multi-omics approach

ABSTRACT: In age-related macular degeneration (AMD), both systemic and local zinc concentrations are decreased. Elevating zinc levels by nutrition or oral supplementation has a positive impact on delaying the progression to end-stage AMD in clinical studies. Here we set out to identify key regulatory pathways involved in this beneficial effect.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Retinal Pigment Epithelial Cell

DISEASE(S): Age Related Macular Degeneration

SUBMITTER: Imre Lengyel

LAB HEAD: Imre Lengyel

PROVIDER: PXD020860 | Pride | 2021-09-09

REPOSITORIES: Pride

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Dataset's files

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			Action	DRS
	DATAdescription.txt	Txt
	FKL2421-S02-A-Secretome_apical_SIMPLEX-Pellet_1.raw	Raw
	FKL2421-S04-A-Secretome_basal_SIMPLEX-Pellet_2.raw	Raw
	FKL2421-S06-A-Secretome_apical_SpeedVac_13.raw	Raw
	FKL2421-S08-A-Secretome_basal_SpeedVac_14.raw	Raw

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A Multi-Omics Approach Identifies Key Regulatory Pathways Induced by Long-Term Zinc Supplementation in Human Primary Retinal Pigment Epithelium.

Emri Eszter E Kortvely Elod E Dammeier Sascha S Klose Franziska F Simpson David D Consortium Eye-Risk ER Den Hollander Anneke I AI Ueffing Marius M Lengyel Imre I

Nutrients 20201006 10

In age-related macular degeneration (AMD), both systemic and local zinc levels decline. Elevation of zinc in clinical studies delayed the progression to end-stage AMD. However, the molecular pathways underpinning this beneficial effect are not yet identified. In this study, we used differentiated primary human fetal retinal pigment epithelium (RPE) cultures and long-term zinc supplementation to carry out a combined transcriptome, proteome and secretome analysis from three genetically different h ...[more]

PMID: 33036197

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Project description:Extracellular vesicles (EV) are cell-secreted, nano-sized membrane particles with various molecular cargo, including metabolites, proteins and nucleic acids [1] . EVs are involved in various physiological and pathological functions, including that of the myocardium [2] , such as cardiac stress adaptation mechanisms [3] . Metabolic co-morbidities can ameliorate the innate stress response of the heart [4], [5] . Furthermore, one of the most common metabolic co-morbidities, type-II diabetes, can inhibit EV- mediated cardioprotection [6] . EVs of high-fat fed animals can also exacerbate ischemic cardiac damage and induce cell death of cardiomyocytes (CM) [7], [8] . Therefore, metabolic diseases might interfere with the effect of cardiac EVs by various mechanisms. However, as of now, little is known about the effect of hypercholesterolemia (HC) on cardiovascular EV communication. Analyzing EVs of the circulation might lead to novel diagnostic tools and to better understanding of disease conditions. As of now it is evidenced that circulating EV number is increased in metabolic diseases [9]–[11] , including familiar hypercholesterolemia [12], [13] , in which their amount is associated with the risk of cardiovascular diseases [14], [15] as well. However, to understand the biological role of EV-related changes in cardiometabolic diseases, characterization of EV composition is needed. The main molecular constituents of EVs are membrane lipids and other metabolites, intravesicular and transmembrane proteins and nucleotides. Change in any of these constituents may result in an altered biological response. Barrachina et. al. has analyzed the dysregulated protein composition of circulating EVs in obesity [16] and in a similar study, miRNA cargo of EVs from obese patients was analyzed, as well [17] , however, it has not been assessed if HC alters EV metabolome, thus, function. EVs contribute to response to various stresses in the myocardium [18] , but as of now, we do not know HC influences EV release of CMs. One of the major effects of HC is cardiac- and systemic inflammation [19] . Earlier studies showed in various disease conditions, such as angiotensin II-induced hypertrophy, that CM EVs activate monocytes, thereby contribute to inflammation [20], [21] . In contrast, in hypoxic conditions, EVs promote macrophage polarization to the reparative M2 phenotype [22], [23] . Thus, we hypothesized that CM EVs might play a role in HC-induced cardiac inflammation. In this study, we aimed to analyze how HC affects the metabolic composition of EVs and how HC modifies CM EV communication. Therefore, we have analyzed the metabolome of circulating EVs of HC- fed rats and compared the identified changes to the plasma metabolome. In addition, for the first time, we assessed how HC affects the biophysical and biochemical properties of CM EVs and we analyzed their role in immune activation.

Project description:Purpose: Age-related degeneration (AMD) is a major cause of blindness in developed countries. The molecular pathogenesis of early events in AMD is poorly understood. We investigated differential gene expression in samples of human retinal pigment epithelium (RPE)/choroid from early AMD and control maculas using exon-based arrays. Methods: Gene expression levels in nine early AMD and nine control human donor eyes were assessed using Affymetrix Human Exon ST 1.0 arrays. Two controls did not pass quality control and were removed. Differentially expressed genes were annotated using DAVID, and gene set enrichment analysis (GSEA) was performed on RPE-specific and endothelium-associated gene sets. CFH genotype was also assessed and differential expression was analyzed with respect to high AMD risk (YH/HH) and low AMD risk (YY) genotypes. Results: Seventy-five genes were identified as differentially expressed (raw p-value < 0.01; >50% fold change, mean log2 expression level in AMD or control M-bM-^IM-% median of all average gene expression values); however, no genes were significant (adj. p-value < 0.01) after correction for multiple hypothesis testing. Of 52 genes with decreased expression in AMD (fold change < 0.5; raw p-value < 0.01), 18 genes were identified by DAVID analysis as associated with vision or neurological processes. GSEA of RPE-associated and endothelium-associated genes revealed a significant decrease in genes typically expressed by endothelial cells in the early AMD group compared to controls, consistent with previous histologic and proteomic studies. Analysis with respect to CFH genotype indicated decreased expression of ADAMTS9 in eyes with high-risk genotypes (fold change = -2.61; raw p-value = 0.0008). Conclusions: GSEA results suggest that RPE transcripts are preserved or elevated in early AMD, concomitant with loss of endothelial cell marker expression. These results are consistent with the notion that choroidal endothelial cell dropout occurs early in the pathogenesis of AMD. Using AltAnalyze (ver. 2.0.7 beta), we analyzed nine early AMD and nine control eyes using Affymetrix Human Exon ST 1.0 arrays. Following initial processing in AltAnalyze, two control arrays were identified as potential outliers by tests implement in arrayQualityMetrics, a package for R.

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Publications

A Multi-Omics Approach Identifies Key Regulatory Pathways Induced by Long-Term Zinc Supplementation in Human Primary Retinal Pigment Epithelium.

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