Identification of ferroptosis-related molecular markers in glomeruli and tubulointerstitium of lupus nephritis

Abstract

Purpose Ferroptosis, characterized by iron accumulation and lipid peroxidation, is a newly demonstrated form of programed cell death. Present studies reveal that ferroptosis is involved in tumor and neurodegenerative disease. Regarding its roles in the development of LN, it is least interrogated. In this study, we explored whether ferroptosis is activated and how does it change at transcriptomic level in LN. Methods 4-Hydroxynonenal (4-HNE) was stained to explore whether ferroptosis is activated. Subsequently, by using bioinformatic methods, public GSE32591 dataset was analyzed. Ferroptosis-related differentially expressed genes (FR-DEGs) were identified in both glomeruli and tubulointerstitium. Immune cell infiltration was evaluated. Correlation between FR-DEGs and infiltrated immune cells was also calculated. Finally, dataset of GSE113342, qPCR, and immunofluorescence staining were also used or performed to validate the results. Results Expression of 4-HNE was significantly increased in both glomeruli and tubulointerstitium. At transcriptomic level, 19 FR-DEGs in glomeruli and 15 FR-DEGs in tubulointerstitium including genes of iron metabolism, antioxidant system inhibitors, and ferroptosis suppressors were significantly altered in LN. Of which, LTF, CYBB, and CCL5 were upregulated and G0S2 and AKR1C1 were downregulated in both glomeruli and tubulointerstitium of LN. qPCR further validated the alteration of LTF, CYBB, CCL5, G0S2, and AKR1C1 in the whole kidney. Correlation analysis showed that CYBB positively correlated with monocyte infiltration in glomeruli and positively correlated with response to therapy. Conclusion Lipid peroxidation was aberrantly activated in LN, suggesting the activation of ferroptosis. LTF, CYBB, CCL5, G0S2, and AKR1C1, especially CYBB, might be good biomarkers of ferroptosis in LN.

Using bioinformatics and systems biology methods to identify the mechanism of interaction between COVID-19 and nonalcoholic fatty liver disease

“…Ferroptosis, characterized by iron accumulation and lipid peroxidation, is a newly demonstrated form of programed cell death. [59] There is now evidence that ferroptosis is a major fine-tuning process of tissue damage inhibition and that they may be over-activated as dangerous stimuli in pathologies such as NAFLD/ NASH . [60] At the same time, NAFLD progression may include exaggerated production of ROS and NO derivatives.…”

Investigation of ferroptosis-associated molecular subtypes and immunological characteristics in lupus nephritis based on artificial neural network learning

“…Bioinformatics analysis based on microarray datasets indicates that ferroptosis-related genes were closely related to the onset of LN [13]. However, the latest study only disclosed the relationship between ferroptosis-related genes and LN, the potential molecular mechanisms by which ferroptosis regulates LN progression still remain obscure.…”

“…Accumulating evidence suggests that ferroptosis is closely related to the onset and progression of diverse kidney diseases, including acute kidney injury (AKI) and chronic kidney disease (CKD) [9][10][11][12], revealing that targeting ferroptosis might be a hopeful therapeutic strategy for kidney diseases. On the basis of bioinformatics analysis, the latest study has determined several ferroptosis-related biomarkers as inhibitors or drivers during the progression of LN [13]. Moreover, another study demonstrates that iron imbalance in the proximal tubules enables to the promotion the accumulation of lipid hydroperoxides, and these iron-catalyzed oxidants can subsequently activate protein-and autoantibody-induced in ammatory transcription factors, ultimately leading to the production of stromal cells and cytokine/chemokine, and enhanced immune cell in ltration levels [14].…”

Kidney tubular epithelial cell ferroptosis links glomerular injury to tubulointerstitial pathology in lupus nephritis

“…Ferroptosis is an iron-dependent form of oxidative injury primarily studied in acute tubular injury in the kidneys (18,31,32). Using bioinformatics and public dataset, a recent study identi ed ferroptosis-related molecular markers in glomeruli and tubulointerstitium of lupus nephritis patients (33). However, majority of the data is not validated and lacks evidence in animal models for intervention.…”