TY  - JOUR
T1  - Identification of hub genes and enriched pathways in renal ischemia–reperfusion injury via integrative transcriptomic and network analysis
TT  - Identification of hub genes and enriched pathways in renal ischemia–reperfusion injury via integrative transcriptomic and network analysis
AU  - Pazarcı, Perçin
AU  - Evyapan, Gülşah
PY  - 2025
DA  - July
Y2  - 2025
DO  - 10.38053/acmj.1713060
JF  - Anatolian Current Medical Journal
JO  - Anatolian Curr Med J / ACMJ / acmj
PB  - MediHealth Academy Yayıncılık
WT  - DergiPark
SN  - 2718-0115
SP  - 459
EP  - 464
VL  - 7
IS  - 4
LA  - en
AB  - Aims: This study aimed to identify key genes and pathways involved in the pathogenesis of renal ischemia–reperfusion injury (IRI)-induced acute kidney injury (AKI) using an integrative bioinformatics approach. Methods: Publicly available gene expression profiles from two independent rat kidney microarray datasets (GSE27274 and GSE58438) were analyzed to identify differentially expressed genes (DEGs) between IRI and control groups. DEGs with an adjusted p-value 1 were considered significant. Common DEGs from both datasets were subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Protein–protein interaction networks were constructed using STRING and cytoscape, and hub genes were identified with the maximal clique centrality algorithm via the CytoHubba plugin. Results: A total of 189 overlapping DEGs were identified (117 upregulated, 72 downregulated). Upregulated DEGs were enriched in pathways associated with glutathione metabolism and oxidative stress response, while downregulated DEGs were associated with DNA replication and inflammatory signaling. Hub genes for upregulated DEGs included Gclc, Gclm, Anpep, and Gss, while downregulated hub genes included Mcm2, Gins1, Pcna, and Tnf. These genes represent potential regulatory nodes in the renal IRI response.Conclusion: This study highlights redox regulation, amino acid metabolism, immune modulation, and cell cycle arrest as major components in the molecular pathogenesis of renal IRI. The identified hub genes may serve as potential diagnostic biomarkers and therapeutic targets. These findings provide a framework for future experimental validation and drug development efforts in AKI caused by IRI.
KW  - Acute kidney injury
KW  - ischemia-reperfusion injury
KW  - hub genes
KW  - oxidative stress
KW  - bioinformatics
N2  - Aims: This study aimed to identify key genes and pathways involved in the pathogenesis of renal ischemia–reperfusion injury (IRI)-induced acute kidney injury (AKI) using an integrative bioinformatics approach. Methods: Publicly available gene expression profiles from two independent rat kidney microarray datasets (GSE27274 and GSE58438) were analyzed to identify differentially expressed genes (DEGs) between IRI and control groups. DEGs with an adjusted p-value 1 were considered significant. Common DEGs from both datasets were subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Protein–protein interaction networks were constructed using STRING and cytoscape, and hub genes were identified with the maximal clique centrality algorithm via the CytoHubba plugin. Results: A total of 189 overlapping DEGs were identified (117 upregulated, 72 downregulated). Upregulated DEGs were enriched in pathways associated with glutathione metabolism and oxidative stress response, while downregulated DEGs were associated with DNA replication and inflammatory signaling. Hub genes for upregulated DEGs included Gclc, Gclm, Anpep, and Gss, while downregulated hub genes included Mcm2, Gins1, Pcna, and Tnf. These genes represent potential regulatory nodes in the renal IRI response.Conclusion: This study highlights redox regulation, amino acid metabolism, immune modulation, and cell cycle arrest as major components in the molecular pathogenesis of renal IRI. The identified hub genes may serve as potential diagnostic biomarkers and therapeutic targets. These findings provide a framework for future experimental validation and drug development efforts in AKI caused by IRI.
CR  - Wang HJ, Varner A, AbouShwareb T, Atala A, Yoo JJ. Ischemia/reperfusion-induced renal failure in rats as a model for evaluating cell therapies. Renal Failure. 2012;34(10):1324-1332. doi:10.3109/0886022x. 2012.725292
CR  - Saat TC, van den Akker EK, JN IJ, Dor FJ, de Bruin RW. Improving the outcome of kidney transplantation by ameliorating renal ischemia reperfusion injury: lost in translation? J Transl Med. 2016;14(1):20. doi: 10.1186/s12967-016-0767-2
CR  - George J, Lu Y, Tsuchishima M, Tsutsumi M. Cellular and molecular mechanisms of hepatic ischemia-reperfusion injury: the role of oxidative stress and therapeutic approaches. Redox Biol. 2024;75:103258. doi:10. 1016/j.redox.2024.103258
CR  - Yuan Y, Sheng P, Ma B, et al. Elucidation of the mechanism of Yiqi Tongluo Granule against cerebral ischemia/reperfusion injury based on a combined strategy of network pharmacology, multi-omics and molecular biology. Phytomedicine. 2023;118:154934. doi:10.1016/j.phymed.2023.154934
CR  - Huang Y, Peng J, Liang Q. Identification of key ferroptosis genes in diabetic retinopathy based on bioinformatics analysis. PloS One. 2023; 18(1):e0280548. doi:10.1371/journal.pone.0280548
CR  - Barrett T, Wilhite SE, Ledoux P, et al. NCBI GEO: archive for functional genomics data sets--update. Nucleic Acids Res. 2013;41(Database issue): D991-995. doi:10.1093/nar/gks1193
CR  - Tang D, Chen M, Huang X, et al. SRplot: a free online platform for data visualization and graphing. PLoS One. 2023;18(11):e0294236. doi:10. 1371/journal.pone.0294236
CR  - Sherman BT, Hao M, Qiu J, et al. DAVID: a web server for functional enrichment analysis and functional annotation of gene lists (2021 update). Nucleic Acids Res. 2022;50(W1):W216–W21. doi:10.1093/nar/gkac194
CR  - Shannon P, Markiel A, Ozier O, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13(11):2498–504. doi:10.1101/gr.1239303
CR  - Chin CH, Chen SH, Wu HH, Ho CW, Ko MT, Lin CY. cytoHubba: identifying hub objects and sub-networks from complex interactome. BMC Syst Biol. 2014;8(Suppl 4):S11. doi:10.1186/1752-0509-8-S4-S11
CR  - Yoon SY, Kim JS, Jeong KH, Kim SK. Acute kidney injury: biomarker-guided diagnosis and management. Medicina (Kaunas). 2022;58(3):340. doi:10.3390/medicina58030340
CR  - Lasorsa F, Rutigliano M, Milella M, et al. Ischemia-reperfusion injury in kidney transplantation: mechanisms and potential therapeutic targets. Int J Mol Sci. 2024;25(8):4332. doi:10.3390/ijms25084332
CR  - Deger M, Akdogan N, Izol V, Kaplan HM, Pazarci P, Aridogan IA. Protective effect of naringin in rat model of renal ischemia reperfusion injury. Rev Nefrol Dial Tras. 2021;41(2):113-118.
CR  - Lu SC. Glutathione synthesis. Biochim Biophys Acta. 2013;1830(5):3143-3153. doi:10.1016/j.bbagen.2012.09.008
CR  - He L, Shi Y. Reduced glutathione ameliorates acute kidney injury by inhibiting ferroptosis. Mol Med Rep. 2023;27(6):123. doi:10.3892/mmr. 2023.13011
CR  - Azarova I, Polonikov A, Klyosova E. Molecular genetics of abnormal redox homeostasis in type 2 diabetes mellitus. Int J Mol Sci. 2023;24(5): 4738. doi:10.3390/ijms24054738
CR  - Ye M, Lin W, Zheng J, Lin S. N-acetylcysteine for chronic kidney disease: a systematic review and meta-analysis. Am J Transl Res. 2021;13(4):2472-2485.
CR  - Aranda-Rivera AK, Cruz-Gregorio A, Amador-Martinez I, et al. Sulforaphane protects from kidney damage during the release of unilateral ureteral obstruction (RUUO) by activating nuclear factor erythroid 2-related factor 2 (Nrf2): role of antioxidant, anti-inflammatory, and antiapoptotic mechanisms. Free Radic Biol Med. 2024;212:49-64. doi:10.1016/j.freeradbiomed.2023.12.022
CR  - Xu B, Zhang P, Tang X, et al. Metabolic rewiring of kynurenine pathway during hepatic ischemia-reperfusion injury exacerbates liver damage by impairing NAD homeostasis. Adv Sci (Weinh). 2022;9(35):e2204697. doi:10.1002/advs.202204697
CR  - Liu YR, Yang NJ, Zhao ML, et al. Hypericum perforatum L. Regulates glutathione redox stress and normalizes Ggt1/anpep signaling to alleviate OVX-induced kidney dysfunction. Front Pharmacol. 2021;12: 628651. doi:10.3389/fphar.2021.628651
CR  - Azizi F, Seifi B, Kadkhodaee M, Ahghari P. Administration of hydrogen sulfide protects ischemia reperfusion-induced acute kidney injury by reducing the oxidative stress. Ir J Med Sci. 2016;185(3):649-654. doi:10. 1007/s11845-015-1328-z
CR  - Bos EM, Wang R, Snijder PM, et al. Cystathionine gamma-lyase protects against renal ischemia/reperfusion by modulating oxidative stress. J Am Soc Nephrol. 2013;24(5):759-770. doi:10.1681/ASN.2012030268
CR  - Zwilling D, Huang SY, Sathyasaikumar KV, et al. Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration. Cell. 2011;145(6):863-874. doi:10.1016/j.cell.2011.05.020
CR  - Kellum JA, Chawla LS. Cell-cycle arrest and acute kidney injury: the light and the dark sides. Nephrol Dial Transplant. 2016;31(1):16-22. doi: 10.1093/ndt/gfv130
CR  - Khan S, Jena G. Valproic acid improves glucose homeostasis by increasing beta-cell proliferation, function, and reducing its apoptosis through HDAC inhibition in juvenile diabetic rat. J Biochem Mol Toxicol. 2016;30(9):438-446. doi:10.1002/jbt.21807
CR  - Frangogiannis NG. Chemokines in the ischemic myocardium: from inflammation to fibrosis. Inflamm Res. 2004;53(11):585-595. doi:10.1007/s00011-004-1298-5
CR  - Mendieta-Condado E, Villasenor-Tapia EC, Galvez-Gastelum FJ, et al. Effects of etanercept on TNF-alpha inhibition in rats with adenine-induced chronic kidney disease. Biomed Res Int. 2022;2022:4970753. doi:10.1155/2022/4970753
CR  - Gaut JP, Liapis H. Acute kidney injury pathology and pathophysiology: a retrospective review. Clin Kidney J. 2021;14(2):526-536. doi:10.1093/ckj/sfaa142
CR  - Tian C, Gao L, Zhang A, Hackfort BT, Zucker IH. Therapeutic effects of Nrf2 activation by bardoxolone methyl in chronic heart failure. J Pharmacol Exp Ther. 2019;371(3):642-651. doi:10.1124/jpet.119.261792
CR  - Xu X, Wang JT, Li M, Liu Y. TIMELESS suppresses the accumulation of aberrant CDC45.MCM2-7.GINS replicative helicase complexes on human chromatin. J Biol Chem. 2016;291(43):2254422558. doi:10.1074/jbc.M116.719963
UR  - https://doi.org/10.38053/acmj.1713060
L1  - https://dergipark.org.tr/tr/download/article-file/4931372
ER  -