5-Methoxytryptophan Alleviates Lipopolysaccharide-Induced Acute Kidney Injury by Regulating Nrf2-Mediated Mitophagy

Xue Sun,1– 4 Hanyu Wang,4 Yang Liu,2 Yanyan Yang,2,3 Yanjun Wang,2,3 Yan Liu,1,4 Shaozheng Ai,2,3 Zhenzhen Shan,1,4 Pengli Luo2,3 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; 2Affiliated Hospital of Qinghai University, Xining, 810000, People’s Republic of China; 3Clinical Research Center for Chronic Kidney Disease in Qinghai Province, Xining, 810000, People’s Republic of China; 4Qinghai University, Xining, 810000, People’s Republic of ChinaCorrespondence: Pengli Luo, The Affiliated Hospital of Qinghai University, No. 29 Tongren Road, Xining, 810000, People’s Republic of China, Tel +8615297093191, Email [email protected]: 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. Keywords: sepsis-induced acute kidney injury1, 5-methoxytryptophan2, Nrf23, mitophagy4, oxidative stress5