{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T12:31:24Z","timestamp":1793017884063,"version":"4.5.0"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,12,7]],"date-time":"2022-12-07T00:00:00Z","timestamp":1670371200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Systemic inflammation and immune response are involved in the pathogenesis of diabetic nephropathy (DN). However, the specific immune-associated signature during DN development is unclear. Our study aimed to reveal the roles of immune-related genes during DN progression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The GSE30529 and GSE30528 datasets were acquired from the Gene Expression Omnibus (GEO) database. Then, the intersection between differentially expressed genes (DEGs) and immune score-related genes (ISRGs) was screened. Subsequently, functional enrichment analyses were performed. The different immune phenotype-related subgroups were finally divided using unsupervised clustering. The core genes were identified by WGCNA and the protein-protein interaction (PPI) network. xCell algorithm was applied to assess the proportion of immune cell infiltration.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>92 immune score-related DEGs (ISRDEGs) were identified, and these genes were enriched in inflammation- and immune-associated pathways. Furthermore, two distinct immune-associated subgroups (C1 and C2) were identified, and the C1 subgroup exhibited activated immune pathways and a higher percentage of immune cells compared to the C2 subgroup. Two core genes (LCK and HCK) were identified and all up-regulated in DN, and the expressions were verified using GSE30122, GSE142025, and GSE104954 datasets. GSEA indicated the core genes were mainly enriched in immune-related pathways. Correlation analysis indicated LCK and HCK expressions were positively correlated with aDC, CD4+ Tem, CD8+T cells, CD8+ Tem, and mast cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We identified two immune-related genes and two immune-associated subgroups, which might help to design more precise tailored immunotherapy for DN patients.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2022.1048139","type":"journal-article","created":{"date-parts":[[2022,12,7]],"date-time":"2022-12-07T06:16:08Z","timestamp":1670393768000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":27,"title":["Bioinformatics analysis identifies immune-related gene signatures and subtypes in diabetic nephropathy"],"prefix":"10.3389","volume":"13","author":[{"given":"Kunna","family":"Lu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanghong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinhuan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingfeng","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,12,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)32064-5","article-title":"Chronic kidney disease","volume":"389","author":"Webster","year":"2017","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1053\/j.ajkd.2017.10.026","article-title":"Update on diabetic nephropathy: Core curriculum 2018","volume":"71","author":"Umanath","year":"2018","journal-title":"Am J Kidney Dis"},{"key":"B3","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1053\/j.ajkd.2019.10.005","article-title":"KDOQI US commentary on the 2017 KDIGO clinical practice guideline on the evaluation and care of living kidney donors","volume":"75","author":"Mandelbrot","year":"2020","journal-title":"Am J Kidney Dis"},{"key":"B4","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1111\/jdi.12533","article-title":"Clinical predictive factors in diabetic kidney disease progression","volume":"8","author":"Radcliffe","year":"2017","journal-title":"J Diabetes Investig"},{"key":"B5","doi-asserted-by":"publisher","first-page":"8637138","DOI":"10.1155\/2017\/8637138","article-title":"Classification and differential diagnosis of diabetic nephropathy","volume":"2017","author":"Qi","year":"2017","journal-title":"J Diabetes Res"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1159\/000489913","article-title":"Effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on all-cause mortality and renal outcomes in patients with diabetes and albuminuria: A systematic review and meta-analysis","volume":"43","author":"Wang","year":"2018","journal-title":"Kidney Blood Press Res"},{"key":"B7","doi-asserted-by":"publisher","first-page":"m4573","DOI":"10.1136\/bmj.m4573","article-title":"Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: Systematic review and network meta-analysis of randomised controlled trials","volume":"372","author":"Palmer","year":"2021","journal-title":"Bmj"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1042\/CS20120198","article-title":"Inflammation and the pathogenesis of diabetic nephropathy","volume":"124","author":"Wada","year":"2013","journal-title":"Clin Sci (Lond)"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.2147\/DDDT.S291591","article-title":"Role of oxidative stress and reduced endogenous hydrogen sulfide in diabetic nephropathy","volume":"15","author":"Hussain Lodhi","year":"2021","journal-title":"Drug Des Devel Ther"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21082806","article-title":"Macrophage phenotype and fibrosis in diabetic nephropathy","volume":"21","author":"Calle","year":"2020","journal-title":"Int J Mol Sci"},{"key":"B11","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1038\/nrneph.2015.175","article-title":"Innate immunity in diabetes and diabetic nephropathy","volume":"12","author":"Wada","year":"2016","journal-title":"Nat Rev Nephrol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1007\/s11255-020-02545-4","article-title":"Autophagy in diabetic nephropathy: A review","volume":"52","author":"Koch","year":"2020","journal-title":"Int Urol Nephrol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1038\/nrneph.2018.9","article-title":"Mitochondrial dysfunction in diabetic kidney disease","volume":"14","author":"Forbes","year":"2018","journal-title":"Nat Rev Nephrol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.958790","article-title":"Immune responses in diabetic nephropathy: Pathogenic mechanisms and therapeutic target","volume":"13","author":"Chen","year":"2022","journal-title":"Front Immunol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1146\/annurev.pathol.4.110807.092150","article-title":"A glimpse of various pathogenetic mechanisms of diabetic nephropathy","volume":"6","author":"Kanwar","year":"2011","journal-title":"Annu Rev Pathol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/s41581-019-0234-4","article-title":"Innate immunity in diabetic kidney disease","volume":"16","author":"Tang","year":"2020","journal-title":"Nat Rev Nephrol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1042\/CS20160636","article-title":"Diabetic nephropathy - is this an immune disorder","volume":"131","author":"Tesch","year":"2017","journal-title":"Clin Sci (Lond)"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1908706116","article-title":"The single-cell transcriptomic landscape of early human diabetic nephropathy","volume":"116","author":"Wilson","year":"2019","journal-title":"Proc Natl Acad Sci USA"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1841690","DOI":"10.1155\/2016\/1841690","article-title":"Immune cells and inflammation in diabetic nephropathy","volume":"2016","author":"Zheng","year":"2016","journal-title":"J Diabetes Res"},{"key":"B20","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1186\/s12882-022-02906-4","article-title":"The landscape of immune cell infiltration in the glomerulus of diabetic nephropathy: Evidence based on bioinformatics","volume":"23","author":"Zhou","year":"2022","journal-title":"BMC Nephrol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"107446","DOI":"10.1016\/j.intimp.2021.107446","article-title":"IDO1 as a new immune biomarker for diabetic nephropathy and its correlation with immune cell infiltration","volume":"94","author":"Yu","year":"2021","journal-title":"Int Immunopharmacol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1080\/21655979.2021.1976540","article-title":"Identification and verification of vascular cell adhesion protein 1 as an immune-related hub gene associated with the tubulointerstitial injury in diabetic kidney disease","volume":"12","author":"Jia","year":"2021","journal-title":"Bioengineered"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1080\/21655979.2021.1960766","article-title":"Identification of fibronectin 1 (FN1) and complement component 3 (C3) as immune infiltration-related biomarkers for diabetic nephropathy using integrated bioinformatic analysis","volume":"12","author":"Wang","year":"2021","journal-title":"Bioengineered"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv007","article-title":"Limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu375","article-title":"Preserving biological heterogeneity with a permuted surrogate variable analysis for genomics batch correction","volume":"30","author":"Parker","year":"2014","journal-title":"Bioinformatics"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1007\/s10528-021-10062-x","article-title":"An integrated data analysis of mRNA, miRNA and signaling pathways in pancreatic cancer","volume":"59","author":"Sohrabi","year":"2021","journal-title":"Biochem Genet"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-0716-0327-7_19","article-title":"Cell-type enrichment analysis of bulk transcriptomes using xCell","volume":"2120","author":"Aran","year":"2020","journal-title":"Methods Mol Biol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0029578","article-title":"Unsupervised analysis of classical biomedical markers: Robustness and medical relevance of patient clustering using bioinformatics tools","volume":"7","author":"Markovich Gordon","year":"2012","journal-title":"PLoS One"},{"key":"B29","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1186\/1471-2105-9-559","article-title":"WGCNA: An r package for weighted correlation network analysis","volume":"9","author":"Langfelder","year":"2008","journal-title":"BMC Bioinf"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2021.760225","article-title":"Identification of immune-related key genes in ovarian cancer based on WGCNA","volume":"12","author":"Quan","year":"2021","journal-title":"Front Genet"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: An r package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"Omics"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.29210","article-title":"Identification of a six-gene prognostic signature for oral squamous cell carcinoma","volume":"235","author":"Wang","year":"2020","journal-title":"J Cell Physiol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"S11","DOI":"10.1186\/1752-0509-8-S4-S11","article-title":"cytoHubba: Identifying hub objects and sub-networks from complex interactome","volume":"8","author":"Chin","year":"2014","journal-title":"BMC Syst Biol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bty271","article-title":"GSEA-InContext: identifying novel and common patterns in expression experiments","volume":"34","author":"Powers","year":"2018","journal-title":"Bioinformatics"},{"key":"B35","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1111\/dom.14007","article-title":"An updated overview of diabetic nephropathy: Diagnosis, prognosis, treatment goals and latest guidelines","volume":"22","author":"Selby","year":"2020","journal-title":"Diabetes Obes Metab"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2021.657918","article-title":"Bioinformatics analysis reveals crosstalk among platelets, immune cells, and the glomerulus that may play an important role in the development of diabetic nephropathy","volume":"8","author":"Yao","year":"2021","journal-title":"Front Med"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2005080859","article-title":"Leukocyte recruitment and vascular injury in diabetic nephropathy","volume":"17","author":"Galkina","year":"2006","journal-title":"J Am Soc Nephrol JASN"},{"key":"B38","doi-asserted-by":"publisher","first-page":"308","DOI":"10.1186\/s12882-020-01960-0","article-title":"Renal expression of cytokines and chemokines in diabetic nephropathy","volume":"21","author":"Ara\u00fajo","year":"2020","journal-title":"BMC Nephrol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21093172","article-title":"The role of chemokines and chemokine receptors in diabetic nephropathy","volume":"21","author":"Chang","year":"2020","journal-title":"Int J Mol Sci"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1007\/s12195-016-0438-7","article-title":"Predictive model of lymphocyte-specific protein tyrosine kinase (LCK) autoregulation","volume":"9","author":"Rohrs","year":"2016","journal-title":"Cell Mol Bioeng"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2018.10.002","article-title":"Exploration of the therapeutic aspects of lck: A kinase target in inflammatory mediated pathological conditions","volume":"108","author":"Kumar Singh","year":"2018","journal-title":"BioMed Pharmacother"},{"key":"B42","doi-asserted-by":"publisher","first-page":"2339","DOI":"10.1038\/s41598-017-02553-y","article-title":"Low level of lck kinase in Th2 cells limits expression of CD4 co-receptor and S73 phosphorylation of transcription factor c-jun","volume":"7","author":"Shebzukhov","year":"2017","journal-title":"Sci Rep"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.14336\/AD.2019.0218","article-title":"Novel role of lck in leptin-induced inflammation and implications for renal aging","volume":"10","author":"Kim","year":"2019","journal-title":"Aging Dis"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/s41390-019-0436-2","article-title":"LCK rs10914542-G allele associates with type 1 diabetes in children Via T cell hyporesponsiveness","volume":"86","author":"Zhu","year":"2019","journal-title":"Pediatr Res"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.2337\/db15-0638","article-title":"\u03b2ig-h3 represses T-cell activation in type 1 diabetes","volume":"64","author":"Patry","year":"2015","journal-title":"Diabetes"},{"key":"B46","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1084\/jem.20020873","article-title":"Constitutive activation of the SRC family kinase hck results in spontaneous pulmonary inflammation and an enhanced innate immune response","volume":"196","author":"Ernst","year":"2002","journal-title":"J Exp Med"},{"key":"B47","doi-asserted-by":"publisher","first-page":"154748","DOI":"10.1016\/j.metabol.2021.154748","article-title":"Inhibition of NLRP3 inflammasome ameliorates podocyte damage by suppressing lipid accumulation in diabetic nephropathy","volume":"118","author":"Wu","year":"2021","journal-title":"Metabolism"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2020.581011","article-title":"Hematopoietic cell kinase (HCK) is essential for NLRP3 inflammasome activation and lipopolysaccharide-induced inflammatory response In vivo","volume":"11","author":"Kong","year":"2020","journal-title":"Front Pharmacol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2016020238","article-title":"Genomic analysis of kidney allograft injury identifies hematopoietic cell kinase as a key driver of renal fibrosis","volume":"28","author":"Wei","year":"2017","journal-title":"J Am Soc Nephrol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.75.4.1949-1957.2001","article-title":"Role of hck in the pathogenesis of encephalomyocarditis virus-induced diabetes in mice","volume":"75","author":"Choi","year":"2001","journal-title":"J Virol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.2174\/1566523218666180214100351","article-title":"Role of immune cells in diabetic kidney disease","volume":"17","author":"Yang","year":"2017","journal-title":"Curr Gene Ther"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1159\/000334928","article-title":"Aberrant recruitment and activation of T cells in diabetic nephropathy","volume":"35","author":"Moon","year":"2012","journal-title":"Am J Nephrol"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1038\/nrneph.2017.138","article-title":"B cells in type 1 diabetes mellitus and diabetic kidney disease","volume":"13","author":"Smith","year":"2017","journal-title":"Nat Rev Nephrol"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2018.08.066","article-title":"Mast cell population in the development of diabetic nephropathy: Effects of renin angiotensin system inhibition","volume":"107","author":"de Morais","year":"2018","journal-title":"Biomedicine pharmacotherapy = Biomedecine pharmacotherapie"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-011-2391-2","article-title":"Pathogenic role of mast cells in the development of diabetic nephropathy: A study of patients at different stages of the disease","volume":"55","author":"Zheng","year":"2012","journal-title":"Diabetologia"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22147554","article-title":"Role of dendritic cell in diabetic nephropathy","volume":"22","author":"Kim","year":"2021","journal-title":"Int J Mol Sci"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2022.1048139\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,7]],"date-time":"2022-12-07T06:16:11Z","timestamp":1670393771000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2022.1048139\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,7]]},"references-count":56,"alternative-id":["10.3389\/fendo.2022.1048139"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2022.1048139","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,7]]},"article-number":"1048139"}}