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Elevated FTO alleviates sepsis‑induced acute kidney injury by regulating macrophage inflammatory phenotypes
Xiaona Chen1, Ziqi Sun2, Jiabo Chen2
1School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, P.R. China.
Abstract:
Studies have linked the dysregulation of N6‑methyladenosine (m6A) to sepsis‑induced acute kidney injury (SAKI), highlighting the persistent challenge of managing excessive proinflammatory cytokine production and subsequent organ dysfunction. The present study, by analyzing the GSE32707 and GSE69063 datasets, found that fat mass and obesity‑associated protein (FTO) was the sole m6A‑related gene markedly downregulated in the peripheral blood transcriptome of patients with sepsis. It further demonstrated that septic mice subjected to cecal ligation and puncture presented increased m6A modifications and reduced FTO expression in both renal tissues and peritoneal macrophages. The findings revealed that increased levels of FTO was associated with reduced mortality and kidney damage during sepsis and that the upregulation of FTO in lipopolysaccharide‑stimulated macrophages led to decreased production of proinflammatory cytokines. Mechanistically, through multiomic analysis of macrophages, the present study identified a novel mechanism involving matrix metalloproteinase 9 (MMP‑9) as a direct target of FTO, which positively affects its translation efficacy. Furthermore, both in vivo and in vitro data confirmed that reduced MMP‑9 levels exerted adverse effects on mitigating inflammatory responses and alleviating renal injury. Overall, the findings underscored the critical role of the FTO/m6A/MMP‑9 axis in the regulation of proinflammatory secretion and improved our understanding of the transcriptomic landscape during the progression of SAKI, suggesting that targeting the FTO/m6A/MMP‑9 axis may offer therapeutic potential for mitigating renal injury in septic patients.
Insights
Fat mass and obesity-associated protein (FTO) is downregulated in sepsis-induced acute kidney injury (SAKI). Restoring FTO levels reduces inflammation and kidney damage by targeting matrix metalloproteinase 9 (MMP-9).
Area of Science:
- Molecular Biology
- Immunology
- Nephrology
Background:
- Sepsis-induced acute kidney injury (SAKI) involves dysregulated N6-methyladenosine (m6A) modification, leading to excessive inflammation and organ damage.
- Fat mass and obesity-associated protein (FTO) is an m6A demethylase implicated in various biological processes.
- Identifying key molecular regulators in SAKI is crucial for developing effective therapeutic strategies.
Purpose of the Study:
- To investigate the role of FTO and its associated m6A pathway in SAKI.
- To elucidate the molecular mechanism by which FTO influences inflammation and kidney injury during sepsis.
- To explore the therapeutic potential of targeting the FTO/m6A axis in SAKI.
Main Methods:
- Bioinformatic analysis of transcriptomic datasets (GSE32707, GSE69063) from sepsis patients.
- In vivo studies using a cecal ligation and puncture (CLP) model in mice to assess FTO expression and m6A modification in renal tissues and peritoneal macrophages.
- In vitro experiments involving lipopolysaccharide (LPS)-stimulated macrophages to evaluate the impact of FTO on cytokine production and MMP-9 translation.
- Multiomic analysis to identify direct targets of FTO.
Main Results:
- FTO was significantly downregulated in the peripheral blood of sepsis patients and in the kidneys and macrophages of septic mice.
- Increased FTO levels correlated with reduced mortality and kidney damage in septic mice.
- Upregulation of FTO in macrophages decreased proinflammatory cytokine production.
- Matrix metalloproteinase 9 (MMP-9) was identified as a direct translational target of FTO.
- Reduced MMP-9 levels exacerbated inflammatory responses and renal injury in both in vivo and in vitro models.
Conclusions:
- The FTO/m6A/MMP-9 axis plays a critical role in regulating proinflammatory cytokine secretion during SAKI.
- FTO downregulation contributes to renal injury in sepsis through increased MMP-9 translation.
- Targeting the FTO/m6A/MMP-9 pathway presents a promising therapeutic strategy for mitigating kidney damage in sepsis.
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