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Spontaneous Neutrophil Extracellular Traps Release Are Inflammatory Markers Associated with Hyperglycemia and Renal Failure on Diabetic Retinopathy.

ABSTRACT: Diabetic retinopathy (DR) is the major microvascular complication of diabetes and causes vitreous traction and intraretinal hemorrhages leading to retinal detachment and total blindness. The evolution of diabetes is related to exacerbating inflammation caused by hyperglycemia and activation of inflammatory cells. Neutrophils are cells able to release structures of extracellular DNA and proteolytic enzymes called extracellular traps (NETs), which are associated with the persistence of inflammation in chronic pathologies. The purpose of the study was to determine the usefulness of neutrophil traps as indicators of DR progression in patients with type 2 diabetes (T2DM). We performed a case-control study of seventy-four cases classified into five groups (non-proliferative DR, mild, moderate, severe, and proliferative) and fifteen healthy controls. We found correlations between NETs and a diagnostic time of T2DM (r = 0.42; p < 0.0001), fasting glucose (r = 0.29; p < 0.01), glycated hemoglobin (HbA1c) (r = 0.31; p < 0.01), estimated glomerular filtration rate (eGFR) (r = -0.29; p < 0.01), and plasma osmolarity (r = 0.25; p < 0.01). These results suggest that due to NETs being associated with clinical indicators, such as HbA1c and eGFR, and that NETs are also associated with DR, clinical indicators might be explained in part through an NET-mediated inflammation process.

SUBMITTER: Magana-Guerrero FS

PROVIDER: S-EPMC10376331 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Spontaneous Neutrophil Extracellular Traps Release Are Inflammatory Markers Associated with Hyperglycemia and Renal Failure on Diabetic Retinopathy.

Magaña-Guerrero Fátima Sofía FS Aguayo-Flores José Eduardo JE Buentello-Volante Beatriz B Zarco-Ávila Karla K Sánchez-Cisneros Paola P Castro-Salas Ilse I De la Torre-Galván Enya E Rodríguez-Loaiza José Luis JL Jiménez-Corona Aida A Garfias Yonathan Y

Biomedicines 20230622 7

Diabetic retinopathy (DR) is the major microvascular complication of diabetes and causes vitreous traction and intraretinal hemorrhages leading to retinal detachment and total blindness. The evolution of diabetes is related to exacerbating inflammation caused by hyperglycemia and activation of inflammatory cells. Neutrophils are cells able to release structures of extracellular DNA and proteolytic enzymes called extracellular traps (NETs), which are associated with the persistence of inflammatio ...[more]

PMID: 37509431

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Project description:SummaryIn the development of diabetic retinopathy (DR), neutrophil infiltration hastens the adhesion between neutrophils and endothelial cells, leading to inflammation. Meanwhile, neutrophil extracellular traps (NETs) produced by neutrophils could clear aging blood vessels, setting the stage for retinal vascular regeneration. To explore the mechanism of NETs-related genes in DR, the transcriptome of NETs from normal and DR individuals were analyzed with gene sequencing and mendelian randomization (MR) analysis. Five NETs-related genes were identified as key genes. Among these genes, CLIC3, GBP2, and P2RY12 were found to be risk factors for Proliferative DR(PDR), whereas HOXA1 and PSAP were protective factors. Further verification by qRT-PCR recognized GBP2, P2RY12 and PSAP as NETs-associated biomarkers in PDR.PurposeTo investigate neutrophil extracellular traps (NETs) related genes as biomarkers in the progression of diabetic retinopathy (DR).MethodsWe collected whole blood samples from 10 individuals with DR and 10 normal controls (NCs) for transcriptome sequencing. Following quality control and preprocessing of the sequencing data, differential expression analysis was conducted to identify differentially expressed genes (DEGs) between the DR and NC groups. Candidate genes were then selected by intersecting these DEGs with key module genes identified through weighted gene co-expression network analysis. These candidate genes were subjected to mendelian randomization (MR) analysis, then least absolute shrinkage and selection operator analysis to pinpoint key genes. The diagnostic utility of these key genes was evaluated using receiver operating characteristic curve analysis, and their expression levels were examined. Additional analysis, including nomogram construction, gene set enrichment analysis, drug prediction and molecular docking, were performed to investigate the functions and molecular mechanisms of the key genes. Finally, the expression of key genes was verified by qRT-PCR and biomarkers were identified.ResultsIntersection of 1,004 DEGs with 1,038 key module genes yielded 291 candidate genes. Five key genes were identified: HOXA1, GBP2, P2RY12, CLIC3 and PSAP. Among them, CLIC3, GBP2, and P2RY12 were identified as risk factors for DR, while HOXA1 and PSAP were protective. These key genes demonstrated strong diagnostic performance for DR. With the exception of P2RY12, all other key genes exhibited down-regulation in the DR group. Furthermore, the nomogram incorporating multiple key genes demonstrated superior predictive capacity for DR compared to a single key genes. The identified key genes are involved in oxidative phosphorylation and ribosome functions. Drug predictions targeting P2RY12 suggested prasugrel, ticagrelor, and ticlopidine as potential options owing to their high binding affinity with this key genes. The qRT-PCR results revealed that the results of GBP2, PSAP and P2RY12 exhibited consistent expression patterns with the dataset.ConclusionThis study identified GBP2, P2RY12 and PSAP as NETs-associated biomarkers in the development of PDR, offering new insights for clinical diagnosis and potential treatment strategies for DR.

Project description:Trypanosoma brucei brucei trypomastigotes are classical blood parasites of cattle, these stages might become potential targets for circulating polymorphonuclear neutrophils (PMN). We here investigated NETs extrusion and related oxygen consumption in bovine PMN exposed to motile T. b. brucei trypomastigotes in vitro. Parasite exposure induced PMN activation as detected by enhanced oxygen consumption rates (OCR), extracellular acidification rates (ECAR), and production of total and extracellular reactive oxygen species (ROS). Scanning electron microscopy (SEM) showed that co-cultivation of bovine PMN with motile trypomastigotes resulted in NETs formation within 120 min of exposure. T. b. brucei-induced NETs were confirmed by confocal microscopy demonstrating co-localization of extruded DNA with neutrophil elastase (NE) and nuclear histones. Immunofluorescence analyses demonstrated that trypomastigotes induced different phenotypes of NETs in bovine PMN, such as aggregated NETs (aggNETs), spread NETs (sprNETs), and diffuse NETs (diffNETs) with aggNETs being the most abundant ones. Furthermore, live cell 3D-holotomographic microscopy unveiled detailed morphological changes during the NETotic process. Quantification of T. b. brucei-induced NETs formation was estimated by DNA and nuclear area analysis (DANA) and confirmed enhanced NETs formation in response to trypomastigote stages. Formation of NETs does not result in a decrease of T. b. brucei viability, but a decrease of 26% in the number of motile parasites. Referring the involved signaling pathways, trypomastigote-induced NETs formation seems to be purinergic-dependent, since inhibition via NF449 treatment resulted in a significant reduction of T. b. brucei-triggered DNA extrusion. Overall, future studies will have to analyze whether the formation of aggNETs indeed plays a role in the outcome of clinical disease and bovine African trypanosomiasis-related immunopathological disorders, such as increased intravascular coagulopathy and vascular permeability, often reported to occur in this disease.

Dataset Information

Spontaneous Neutrophil Extracellular Traps Release Are Inflammatory Markers Associated with Hyperglycemia and Renal Failure on Diabetic Retinopathy.

Publications

Spontaneous Neutrophil Extracellular Traps Release Are Inflammatory Markers Associated with Hyperglycemia and Renal Failure on Diabetic Retinopathy.

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