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5-Methoxytryptophan Alleviates Lipopolysaccharide-Induced Acute Kidney Injury by Regulating Nrf2-Mediated Mitophagy
Xue Sun1,2,3,4, Hanyu Wang4, Yang Liu2
1Research Center for High Altitude Medicine, Key Laboratory of High Altitude Medicine(Ministry of Education),Key Laboratory of Application and Foundation for High Altitude Medicine Research in Qinghai Province (Qinghai-Utah Joint Research Key Laboratory for High Altitude Medicine), Qinghai University, Xining, 810000, People's Republic of China.
Purpose:
The effects of 5-methoxytryptophan (5-MTP) on mitophagy in sepsis-induced acute kidney injury (S-AKI) and its possible role in the Nrf2/HO-1 signaling pathway are unclear. In this study, we aimed to examine the levels of serum 5-MTP and mitophagy in patients with S-AKI and to evaluate the influence of 5-MTP on a lipopolysaccharide(LPS)-induced AKI model. Additionally, we sought to elucidate the mechanisms by which 5-MTP regulates mitophagy via Nrf2 mediation.
Patients And Methods:
We initially included 52 patients with sepsis, 25 of whom were diagnosed with AKI, and used metabolomics to analyze the serum levels of 5-MTP. We investigated the effects of exogenous 5-MTP on the kidneys of a mouse model with LPS-induced AKI. We explored the underlying mechanisms by assessing oxidative stress and mitophagy in the kidneys following the administration of different doses of 5-MTP to S-AKI mice. In addition, we used ML385 to inhibit Nrf2 expression and assessed mitophagy levels in kidney damage to investigate the specific mechanism by which 5-MTP mitigates S-AKI.
Results:
The plasma 5-MTP levels were significantly higher in patients with S-AKI than in those with sepsis, showing a correlation with renal function. Administration of 5-MTP led to a decrease in inflammatory and oxidative stress reactions and stimulated the Nrf2 signaling pathway to alleviate kidney injury following the induction of sepsis. However, this protective effect was reversed by ML385. In S-AKI, 5-MTP therapy enhanced mitophagy and decreased kidney injury by upregulating the Nrf2/HO-1 pathway.
Conclusion:
Serum 5-MTP levels correlate with renal function and upregulate Nrf2 expression by activating the Nrf2 signaling pathway, thereby promoting renal tubular mitophagy and alleviating S-AKI.
Insights
Elevated 5-methoxytryptophan (5-MTP) in sepsis-induced acute kidney injury (S-AKI) correlates with kidney function. 5-MTP treatment alleviates S-AKI by enhancing mitophagy via the Nrf2/HO-1 pathway.
Area of Science:
- Nephrology
- Molecular Biology
- Biochemistry
Background:
- Sepsis-induced acute kidney injury (S-AKI) is a critical condition with significant morbidity and mortality.
- The role of 5-methoxytryptophan (5-MTP) and its impact on mitophagy in S-AKI remain largely unexplored.
- Understanding the molecular mechanisms, including the Nrf2/HO-1 signaling pathway, is crucial for developing effective treatments.
Purpose of the Study:
- To investigate serum 5-methoxytryptophan (5-MTP) levels and mitophagy in patients with sepsis-induced acute kidney injury (S-AKI).
- To evaluate the therapeutic effects of 5-MTP on a lipopolysaccharide (LPS)-induced AKI mouse model.
- To elucidate the underlying mechanisms of 5-MTP in regulating mitophagy via Nrf2 mediation in S-AKI.
Main Methods:
- Serum metabolomics analysis to quantify 5-MTP levels in 52 sepsis patients (25 with AKI).
- Administration of exogenous 5-MTP to a mouse model of LPS-induced AKI to assess kidney injury, oxidative stress, and mitophagy.
- Inhibition of Nrf2 expression using ML385 to investigate the specific role of the Nrf2 pathway in 5-MTP's protective effects.
Main Results:
- Serum 5-MTP levels were significantly higher in S-AKI patients and correlated with renal function.
- 5-MTP administration reduced inflammation and oxidative stress, activating the Nrf2 signaling pathway and alleviating kidney injury in S-AKI mice.
- The protective effects of 5-MTP were diminished by ML385, indicating Nrf2-dependent mitigation of kidney damage and enhanced mitophagy.
Conclusions:
- Elevated serum 5-methoxytryptophan (5-MTP) is associated with renal function in sepsis-induced acute kidney injury (S-AKI).
- 5-MTP activates the Nrf2/HO-1 signaling pathway, promoting renal tubular mitophagy and offering a protective effect against S-AKI.
- Targeting 5-MTP and the Nrf2 pathway presents a potential therapeutic strategy for managing S-AKI.
