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pmid:33863396
Bioinformatic analysis identifies potential biomarkers and therapeutic targets of septic-shock-associated acute kidney injury.
Yun Tang · Xiaobo Yang · Huaqing Shu · Yuan Yu · Shangwen Pan · Jiqian Xu · You Shang
Hereditas · 2021 doi:10.1186/s41065-021-00176-y
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Complete file
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Acute kidney injury (AKI) is a common complication of sepsis, and its occurrence is a poor prognostic sign to septic patients. We analyzed co-differentially expressed genes (co-DEGs) to explore relationships between septic shock and AKI and reveal potential biomarkers and therapeutic targets of septic-shock-associated AKI (SSAKI).\nMETHODS: Two gene expression datasets (GSE30718 and GSE57065) were downloaded from the Gene Expression Omnibus (GEO). The GSE57065 dataset included 28 septic shock patients and 25 healthy volunteers and blood samples were collected within 0.5, 24 and 48 h after shock. Specimens of GSE30718 were collected from 26 patients with AKI and 11 control patents. AKI-DEGs and septic-shock-DEGs were identified using the two datasets. Subsequently, Gene Ontology (GO) functional analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and protein-protein interaction (PPI) network analysis were performed to elucidate molecular mechanisms of DEGs. We also evaluated co-DEGs and corresponding predicted miRNAs involved in septic shock and AKI.\nRESULTS: We identified 62 DEGs in AKI specimens and 888, 870, and 717 DEGs in septic shock blood samples within 0.5, 24 and 48 h, respectively. The hub genes of EGF and OLFM4 may be involved in AKI and QPCT, CKAP4, PRKCQ, PLAC8, PRC1, BCL9L, ATP11B, KLHL2, LDLRAP1, NDUFAF1, IFIT2, CSF1R, HGF, NRN1, GZMB, and STAT4 may be associated with septic shock. Besides, co-DEGs of VMP1, SLPI, PTX3, TIMP1, OLFM4, LCN2, and S100A9 coupled with corresponding predicted miRNAs, especially miR-29b-3p, miR-152-3p, and miR-223-3p may be regarded as promising targets for the diagnosis and treatment of SSAKI in the future.\nCONCLUSIONS: Septic shock and AKI are related and VMP1, SLPI, PTX3, TIMP1, OLFM4, LCN2, and S100A9 genes are significantly associated with novel biomarkers involved in the occurrence and development of SSAKI.", "claims": [{"id": "claim-method", "statement": "The “limma” package [17] was utilized to screen out DEGs.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:33863396", "locator": "sections[4] \"Identification of DEGs\" paragraph 2", "quote": "The “limma” package [17] was utilized to screen out DEGs."}], "state": "complete"}, {"id": "claim-data-access", "statement": "All data generated or analysed during this study are included in this published article [and its Supplementary information files].", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:33863396", "locator": "sections[25] \"notes\" paragraph 1", "quote": "All data generated or analysed during this study are included in this published article [and its Supplementary information files]."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": null, "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:33863396"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. 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"rows": [["Genes", "Predicted miRNAs", "Category", "", "P value"], ["SLPI", "hsa-miR-370-3p", "KEGG pathway", "NA", ""], ["hsa-miR-3679-5p", "GO terms", "NA", ""], ["hsa-miR-520a-5p", "", "", ""], ["TIMP1", "hsa-miR-22-3p", "KEGG pathway", "HIF-1 signaling pathway", "9e-05"], ["hsa-miR-4739", "GO terms", "regulation of integrin-mediated signaling pathway", "0.002"], ["hsa-miR-1321", "", "negative regulation of metalloenzyme activity", "0.002"], ["hsa-miR-4756-5p", "", "negative regulation of trophoblast cell migration", "0.002"], ["", "", "negative regulation of membrane protein ectodomain proteolysis", "0.002"], ["", "", "cell activation", "0.005"], ["", "", "metalloendopeptidase inhibitor activity", "0.005"], ["", "", "platelet alpha granule lumen", "0.005"], ["", "", "platelet degranulation", "0.008"], ["", "", "extracellular matrix disassembly", "0.012"], ["", "", "response to peptide hormone", "0.015"], ["PTX3", "hsa-miR-29a-3p", "KEGG pathway", "NA", ""], ["hsa-miR-29b-3p", "GO 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"MESH:D013203", "18.13", "15"], ["IMMUNE SUPPRESSION", "OMIM:146850", "17.92", "4"], ["Kidney Diseases", "MESH:D007674", "274.34", "537"], ["Acute Kidney Injury", "MESH:D058186", "214.94", "463"], ["Renal Insufficiency", "MESH:D051437", "146.23", "153"]], "row_count": 45, "column_count": 5, "numeric_cells": 133, "header_rows": 1, "locator": "section[14]/table-wrap[1]#Tab1"}}, {"id": "asset:table:pmid:33863396:5", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:1b20a148801f8409e37cf53e3d6a2630feeaa18610c6ea14b9a02445a560117c", "bytes": 2822, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[14]/table-wrap[2]#Tab2", "version": null, "note": "The GO terms enrichment for the co-DEGs of septic shock and AKI", "structure": {"pmcid": "PMC8052759", "section_index": 14, "section_title": "Functional enrichment in co-DEGs", "row_count": 48, "column_count": 4}, 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"GO_REF:0000024"], ["extracellular space", "HDA", "PMID:16502470"], ["extracellular exosome", "HDA", "PMID:19056867"], ["iron ion binding", "ISS", "GO_REF:0000024"], ["S100A9", "protein binding", "IPI", "PMID:17620599"], ["extracellular region", "TAS", "PMID:22489132"], ["collagen-containing extracellular matrix", "HDA", "PMID:23979707"], ["extracellular space", "HDA", "PMID:16502470"], ["cytosol", "IDA", "GO_REF:0000052"], ["extracellular exosome", "HDA", "PMID:19056867"], ["antimicrobial humoral immune response mediated by antimicrobial peptide", "IDA", "PMID:12874352"], ["calcium ion binding", "TAS", "PMID:22489132"], ["cytoplasm", "IDA", "PMID:12874352"], ["leukocyte migration involved in inflammatory response", "IDA", "PMID:12626582"], ["neutrophil aggregation", "IDA", "PMID:12626582"], ["neutrophil chemotaxis", "IDA", "PMID:12626582"], ["nucleus", "HDA", "PMID:21630459"]], "row_count": 48, "column_count": 4, "numeric_cells": 48, "header_rows": 1, "locator": "section[14]/table-wrap[2]#Tab2"}}, {"id": "asset:table:pmid:33863396:6", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:ee61ea813d15a6d0bebd061bedce9fdf33c53a204607c22e80759e12b41eaf66", "bytes": 1754, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[15]/table-wrap[1]#Tab3", "version": null, "note": "GO and KEGG pathways enrichment among predicted miRNAs and co-DEGs", "structure": {"pmcid": "PMC8052759", "section_index": 15, "section_title": "GO and KEGG pathway enrichment among predicted miRNAs and co-DEGs", "row_count": 30, "column_count": 5}, "table": {"label": "Table 3", "caption": "GO and KEGG pathways enrichment among predicted miRNAs and co-DEGs", "rows": [["Genes", "Predicted miRNAs", "Category", "", "P value"], ["SLPI", "hsa-miR-370-3p", "KEGG pathway", "NA", ""], ["hsa-miR-3679-5p", "GO terms", "NA", ""], ["hsa-miR-520a-5p", "", "", ""], ["TIMP1", "hsa-miR-22-3p", "KEGG pathway", "HIF-1 signaling pathway", "9e-05"], ["hsa-miR-4739", "GO terms", "regulation of integrin-mediated signaling pathway", "0.002"], ["hsa-miR-1321", "", "negative regulation of metalloenzyme activity", "0.002"], ["hsa-miR-4756-5p", "", "negative regulation of trophoblast cell migration", "0.002"], ["", "", "negative regulation of membrane protein ectodomain proteolysis", "0.002"], ["", "", "cell activation", "0.005"], ["", "", "metalloendopeptidase inhibitor activity", "0.005"], ["", "", "platelet alpha granule lumen", "0.005"], ["", "", "platelet degranulation", "0.008"], ["", "", "extracellular matrix disassembly", "0.012"], ["", "", "response to peptide hormone", "0.015"], ["PTX3", "hsa-miR-29a-3p", "KEGG pathway", "NA", ""], ["hsa-miR-29b-3p", "GO terms", "NA", ""], ["hsa-miR-29c-3p", "", "", ""], ["hsa-miR-101-3p", "", "", ""], ["hsa-miR-144-3p", "", "", ""], ["VMP1", "hsa-miR-19a-3p", "KEGG pathway", "MicroRNAs in cancer", "3e-24"], ["hsa-miR-19b-3p", "", "Proteoglycans in cancer", "0.010"], ["hsa-miR-148a-3p", "GO terms", "autophagic vacuole membrane", "0.008"], ["hsa-miR-152-3p", "", "pre-autophagosomal structure", "0.008"], ["miR-223-3p", "", "cell junction assembly", "0.008"], ["", "", "regulation of autophagy", "0.008"], ["", "", "embryo implantation", "0.009"], ["", "", "cell junction organization", "0.014"], ["", "", "autophagy", "0.017"], ["", "", "single organismal cell-cell adhesion", "0.017"]], "row_count": 30, "column_count": 5, "numeric_cells": 39, "header_rows": 1, "locator": "section[15]/table-wrap[1]#Tab3"}}], "gaps": ["asset:data:geo:GSE30718 not downloaded", "asset:data:geo:GSE30718 licence not read", "asset:data:geo:GSE57065 not downloaded", "asset:data:geo:GSE57065 licence not read"]}, "analysis": {"state": "complete", "methods": [{"id": "method-1", "family": "differential_expression", "specific": "limma_voom", "label": "Differential expression analysis", "dsl_operations": ["normalise_counts", "differential_expression_fit", "fdr_bh"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["count_matrix_with_condition"], "evidence": {"score": 1.0, "band": "verbatim", "quote": "The “limma” package [17] was utilized to screen out DEGs."}}, {"id": "method-2", "family": "network_analysis", "specific": "ppi_network", "label": "Network / pathway analysis", "dsl_operations": ["build_graph", "centrality_scores", "pathway_enrich"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["edge_list"], "evidence": {"score": 0.7, "band": "medium", "quote": "protein-protein interaction"}}, {"id": "method-3", "family": "network_analysis", "specific": "pathway_enrichment", "label": "Network / pathway analysis", "dsl_operations": ["pathway_enrich"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["edge_list"], "evidence": {"score": 0.7, "band": "medium", "quote": "pathway enrichment"}}], "targets": [], "gaps": []}, "capability": {"state": "complete", "requirements": [{"capability_id": "capability:computational_analysis", "label": "Computational analysis platform", "assay_families": ["meta_analysis", "machine_learning", "survival_analysis", "statistical_regression", "pca", "molecular_docking", "network_analysis", "differential_expression", "gwas"], "availability_state": "owned", "tier_unlocked": "R1", "candidate": "Automated Assays Laravel application and simulated adapters"}], "gaps": []}, "readiness": {"state": "complete", "tier": "R1", "blocking_axis": "none", "blocked_on": "nothing:replicable_now", "axes": {"method": {"tier": "R1", "expressible": true, "required_operations": ["normalise_counts", "differential_expression_fit", "fdr_bh"], "missing_operations": [], "basis": "The paper names the method it used and the corpus's method extractor maps it onto the DSL catalogue: limma_voom."}, "capability": {"tier": "R1", "capability_id": "capability:computational_analysis", "availability_state": "owned", "basis": "The computational analysis is owned. The physical bench the paper used is not, so a physical validation cannot be run here."}, "data": {"tier": "R1", "reachable": true, "accessions": ["GSE30718", "GSE57065"], "resolved_accessions": ["GSE30718", "GSE57065"], "statements": ["All data generated or analysed during this study are included in this published article [and its Supplementary information files]."], "basis": "The paper names GSE30718, GSE57065 in Gene Expression Omnibus (GEO) and the accession resolves in the repository. 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