Tocilizumab mimotope alleviates kidney injury and fibrosis by inhibiting IL-6 signaling and ferroptosis in UUO model

Yang, Lin; Guo, Jinsheng; Yu, Nan; Liu, Yuan; Song, Haoming; Niu, Jianying; Gu, Yong

doi:10.1016/j.lfs.2020.118487

Cited by 53 publications

(39 citation statements)

References 35 publications

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“…Six of the 10 hub genes (CA9, HMOX1, IL6, CDKN1A, HIF1A, and MYC) were identified as differentially expressed and diagnostically significant in the GSE52093 dataset and were recognized as key genes involved in the role of ferroptosis in TAAD. All key genes have reliable evidence supporting their involvement in the regulation of ferroptosis in different biological circumstances (20,21), among which CA9, MYC, and CDKN1A function as ferroptosis suppressors (30)(31)(32) and IL6 functions as a ferroptosis promoter (33,34), while HMOX1 and HIF1A can function as both suppressors and promoters of ferroptosis (32,(35)(36)(37)(38). Interestingly, in both datasets we studied, all key genes were upregulated in the TAAD samples, suggesting that the mechanisms of ferroptosis regulation in TAAD may be multiplicative and complicated.…”

Section: Discussionmentioning

confidence: 99%

Role of ferroptosis-related genes in Stanford type a aortic dissection and identification of key genes: new insights from bioinformatic analysis

et al. 2021

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Stanford type A aortic dissection (TAAD) is one of the most dangerous vascular diseases worldwide, and the mechanisms of its development remain unclear. Further molecular pathology studies may contribute to a comprehensive understanding of TAAD and provide new insights into diagnostic markers and potential therapeutic targets. Recent studies have identified that ferroptosis, a form of cell death, may play a previously unrecognized role in influencing the development of TAAD. In this study, we explored the pathological role of ferroptosis in TAAD by performing bioinformatics analyses. Gene set enrichment analysis (GSEA) showed that the ferroptosis-related gene (FRG) set was significantly different between normal and TAAD aortic samples at an overall level (p < 0.001). Further Gene Ontology (GO) enrichment analysis found that FRGs may influence the response to oxygen levels, transition metal ion homeostasis, and the response to hypoxia by regulating oxidoreductase activity and post-transcriptional ubiquitination modifications, which may regulate cellular ferroptosis and contribute to the structural abnormalities that render patients susceptible to TAAD. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed the HIF-1 signaling pathway may be a key pathway regulating cellular ferroptosis in TAAD development. We further identified six key genes (CA9, HMOX1, IL6, CDKN1A, HIF1A, MYC) from differentially expressed FRGs in TAAD by constructing a protein-protein interaction (PPI) network, all key genes were upregulated in TAAD. Four of the key genes (CA9, IL6, CDKN1A, and HIF1A) were demonstrated to be correlated with cigarette smoke extract-induced ferroptosis in aortic vascular smooth muscle cells. These results suggest that ferroptosis is one of the essential pathological processes in the development of TAAD, and some FRGs affect TAAD development by mediating cellular ferroptosis, which provides deepening insights into the molecular mechanisms and potential therapeutic 3 targets of TAAD.

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Section: Discussionmentioning

confidence: 99%

Role of ferroptosis-related genes in Stanford type a aortic dissection and identification of key genes: new insights from bioinformatic analysis

et al. 2021

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“…Most importantly, we uncovered a possible mechanism for the antifibrotic effects of AKF-PD in UUO mice. Nevertheless, all of apoptosis, necroptosis, and ferroptosis have been found in IRI, folic acid-induced AKI, and UUO (Xiao et al, 2017;Popper et al, 2019;Linkermann et al, 2013;Ning et al, 2011;Oberbauer et al, 2001;Ortiz et al, 2000;Hu et al, 2019;Yang et al, 2020;Martin-Sanchez et al, 2018). We still could not completely exclude the influence of AKF-PD on apoptosis or ferroptosis from our in vivo data.…”

Section: Discussionmentioning

confidence: 85%

Fluorofenidone Alleviates Renal Fibrosis by Inhibiting Necroptosis Through RIPK3/MLKL Pathway

et al. 2020

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Cell death and sterile inflammation are major mechanisms of renal fibrosis, which eventually develop into end-stage renal disease. “Necroptosis” is a type of caspase-independent regulated cell death, and sterile inflammatory response caused by tissue injury is strongly related to necrosis. Fluorofenidone (AKF-PD) is a novel compound shown to ameliorate renal fibrosis and associated inflammation. We investigated whether AKF-PD could alleviate renal fibrosis by inhibiting necroptosis. Unilateral ureteral obstruction (UUO) was used to induce renal tubulointerstitial fibrosis in C57BL/6J mice. AKF-PD (500 mg/kg) or necrostatin-1 (Nec-1; 1.65 mg/kg) was administered simultaneously for 3 and 7 days. Obstructed kidneys and serum were harvested after euthanasia. AKF-PD and Nec-1 ameliorated renal tubular damage, inflammatory-cell infiltration, and collagen deposition, and the expression of proinflammatory factors (interlukin-1β, tumor necrosis factor [TNF]-α) and chemokines (monocyte chemoattractant protein-1) decreased. AKF-PD or Nec-1 treatment protected renal tubular epithelial cells from necrosis and reduced the release of lactate dehydrogenase in serum. Simultaneously, production of receptor-interacting protein kinase (RIPK)3 and mixed lineage kinase domain-like protein (MLKL) was also reduced 3 and 7 days after UUO. AKF-PD and Nec-1 significantly decreased the percentage of cell necrosis, inhibiting the phosphorylation of MLKL and RIPK3 in TNF-α- and Z-VAD–stimulated human proximal tubular epithelial (HK-2) cells. In conclusion, AKF-PD and Nec-1 have effective anti-inflammatory and antifibrotic activity in UUO-induced renal tubulointerstitial fibrosis, potentially mediated by the RIPK3/MLKL pathway.

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“…Therefore, the perspective that ferroptosis is considered a therapeutic target for organ fibrosis has been gradually accepted [ 128 , 129 ]. In a recent study involving ferroptosis and UUO-mediated renal fibrosis, researchers found that regulating the ferroptosis signaling pathway can alleviate kidney injury [ 130 ], but they failed to directly prove that ferroptosis is involved in renal fibrosis progression. Therefore, studies on ferroptosis and renal fibrosis remain to be conducted.…”

Section: Ferroptosis and Ckdmentioning

confidence: 99%

The Cross‐Link between Ferroptosis and Kidney Diseases

Wang

Liu

Wang

et al. 2021

Oxidative Medicine and Cellular Longevity

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Acute and chronic kidney injuries result from structural dysfunction and metabolic disorders of the kidney in various etiologies, which significantly affect human survival and social wealth. Nephropathies are often accompanied by various forms of cell death and complex microenvironments. In recent decades, the study of kidney diseases and the traditional forms of cell death have improved. Nontraditional forms of cell death, represented by ferroptosis and necroptosis, have been discovered in the field of kidney diseases, which have reshuffled the role of traditional cell death in nephropathies. Although interactions between ferroptosis and acute kidney injury (AKI) have been continuously explored, studies on ferroptosis and chronic kidney disease (CKD) remain limited. Here, we have reviewed the therapeutic significance of ferroptosis in AKI and anticipated the curative potential of ferroptosis for CKD in the hope of providing insights into ferroptosis and CKD.

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Tocilizumab mimotope alleviates kidney injury and fibrosis by inhibiting IL-6 signaling and ferroptosis in UUO model

Cited by 53 publications

References 35 publications

Role of ferroptosis-related genes in Stanford type a aortic dissection and identification of key genes: new insights from bioinformatic analysis

Role of ferroptosis-related genes in Stanford type a aortic dissection and identification of key genes: new insights from bioinformatic analysis

Fluorofenidone Alleviates Renal Fibrosis by Inhibiting Necroptosis Through RIPK3/MLKL Pathway

The Cross‐Link between Ferroptosis and Kidney Diseases

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