Identification of Genes Reveals the Mechanism of Cell Ferroptosis in Diabetic Nephropathy

Xian Wang; Ling Jiang; Xue-Qi Liu; Yue-Bo Huang; Wei Zhu; Han-Xu Zeng; Li Gao; Li-Juan Ma; Meng-Ya Zhang; Qi-Jin Zhu; Yong-Gui Wu

doi:10.3389/fphys.2022.890566

Identification of Genes Reveals the Mechanism of Cell Ferroptosis in Diabetic Nephropathy

Front Physiol. 2022 May 26:13:890566. doi: 10.3389/fphys.2022.890566. eCollection 2022.

Authors

Xian Wang¹, Ling Jiang¹, Xue-Qi Liu¹, Yue-Bo Huang¹, Wei Zhu¹, Han-Xu Zeng¹, Li Gao¹, Li-Juan Ma¹, Meng-Ya Zhang¹, Qi-Jin Zhu¹, Yong-Gui Wu^{1

2}

Affiliations

¹ Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
² Center for Scientific Research of Anhui Medical University, Hefei, China.

Abstract

Aims/Introduction: Diabetic nephropathy (DN) is one of the main complications of diabetes. Genomics may reveal the essential pathogenesis of DN. We analyzed datasets to search for key genes to explore pathological mechanisms of DN. Materials and Methods: In this study, weighted gene co-expression network analysis (WGCNA) was used to divide the differential expression genes (DEGs) from GSE142025 into different modules, and enrichment pathway analysis was conducted for each module to find key genes related to cell death pathway. Then, verification was carried out through network and histopathology. Finally, the regulatory mechanisms of key gene expression, including transcription factors (TFs), miRNA and E3 ligases related to ubiquitination, were predicted through website prediction and then miRNA results were validated using GSE51674 dataset. Results: The results of WGCNA and enrichment pathway analysis indicated that ferroptosis had significantly occurred in advanced DN (AND) group. Analysis of DEGs indicated that the occurrence and development of ferroptosis are mainly through ALOX15-mediated lipid metabolism pathway, which was found in all intrinsic cells of the glomerulus detected by IHC and IF staining. Moreover, network predictions were used for searching ALOX15-related TFs and ubiquitination. Meanwhile, the network predictions combining with other dataset furtherly discovered miRNAs which regulated ALOX15 expression. This study showed that the levels of mmu-miR-142-3p increased in DN mice kidney tissues, compared with the NC group. Conclusion: Ferroptosis existed in glomerular intrinsic cells of ADN group and its potential key candidate gene was ALOX15 which may be regulated by miR-142 and miRNA-650, TFs (CREBBP, EP300, HDAC1, MTA1, SPI1, STAT6) and E3 ligases related to ubiquitination (PML, ZMIZ1, MARCHF1, MARCHF3, MARCHF8, MARCHF11).

Keywords: diabetic nephropathy; ferroptosis; gene; glomerulus; transcriptome; weighted gene co-expression network analysis.