• Haiming Wen, Jun Liu, Chaona Wang, Shu Yan, Zhaoyu Li, Wei Lan, Hongtao Liu, and Shaopeng Ming.
• The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
• J. Investig. Med. 2024 Sep 26: 1081558924128851810815589241288518.

AbstractKidney transplantation is a pivotal treatment for end-stage renal disease (ESKD). However, renal ischemia-reperfusion injury (IRI) during surgery significantly impacts graft function. Despite unclear molecular mechanisms, no specific therapies or preventative measures are available. Gene expression profiles from renal biopsies before and after IRI were downloaded from public databases. Differentially expressed genes (DEGs) were identified using the Wilcoxon rank-sum test and weighted gene co-expression network analysis. Ferroptosis-associated genes were screened using the FerrDb database. The genes with the highest connectivity were identified via the PPI network, and upstream regulatory miRNAs were found through the gene-miRNA network. A mouse renal IRI model was constructed for transcriptome sequencing and qRT-PCR validation to elucidate the relationship between key ferroptosis genes and regulatory miRNAs in renal IRI. Differential analysis identified 15 ferroptosis-associated genes (TNFAIP3, IL6, KLF2, EGR1, JUN, ZFP36, GDF15, CDKN1A, HSPB1, BRD2, PDK4, DUSP1, SLC2A3, DDIT3, CXCL2) involved in renal IRI regulation. In animal experiments, ferroptosis-related genes were also upregulated in the model group. Enrichment analysis and H&E pathological staining suggested these genes are primarily involved in renal inflammatory responses. PPI network analysis revealed IL6 as the gene with the highest connectivity, and the gene-miRNA network indicated IL6 might be regulated by miR-let-7a. Animal experiments revealed decreased miR-let-7a and increased IL6 levels in the model group, identifying potential therapeutic targets. MiR-let-7a regulates ferroptosis in renal IRI by targeting IL6, highlighting IL6 as a crucial gene in the ferroptosis process of renal IRI.

4 keywords...

hide…