Levistolide a Attenuates Acute Kidney Injury in Mice by Inhibiting the TLR-4/NF-κB Pathway

Jiahui Shi,1 Shuangwei Li,1 Langping Yi,1 Minghuang Gao,1 Jiaying Cai,1 Cong Yang,1 Yujie Ma,1 Yousheng Mo,2 Qi Wang1 1Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China; 2Department of Hepatology, Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of ChinaCorrespondence: Yousheng Mo; Qi Wang, Email [email protected]; [email protected]: Acute kidney injury (AKI) is characterized by a significant reduction in kidney function and the accumulation of metabolites such as Creatinine (CRE) and Blood Urea Nitrogen (BUN). Levistolide A (LA), an active component of Ligusticum chuanxiong, offers multiple therapeutic benefits, including cardiovascular and neuroprotection, antitumor and analgesic effects, as well as anti-inflammatory, antioxidant, antifibrotic, and proapoptotic actions. However, the underlying mechanism of LA in treating AKI has not been fully elucidated.Methods: In this study, we established a glycerol-induced AKI model in mice to evaluate the protective effects of LA. Renal function was assessed by measuring levels of CRE and BUN. Histological analyses were performed to evaluate kidney tissue damage. Additionally, oxidative stress markers, apoptosis indicators, inflammatory cell infiltration, and inflammatory mediator levels were assessed. The involvement of the TLR-4/NF-κB signaling pathway was investigated through molecular assays.Results: LA treatment significantly ameliorated glycerol-induced AKI in mice, evidenced by reduced levels of CRE and BUN. Histological examination revealed decreased renal tissue damage in LA-treated groups. LA exerted antioxidant effects by increasing the levels of Glutathione (GSH) and Superoxide Dismutase (SOD), while reducing Reactive Oxygen Species (ROS) accumulation. Apoptosis in renal tissues was attenuated, as indicated by decreased caspase-3 activation. Furthermore, LA reduced the infiltration of inflammatory cells and the release of inflammatory mediators such as TNF-α and IL-6. Mechanistically, LA suppressed the inflammatory response by inhibiting the TLR-4/NF-κB signaling pathway, as demonstrated by reduced NF-κB activation and decreased expression of TLR-4.Conclusion: Levistolide A mitigates acute kidney injury through its antioxidative properties and modulation of the TLR-4/NF-κB signaling pathway. These findings provide valuable insights into the therapeutic potential of LA for AKI treatment and lay the groundwork for further mechanistic studies.Keywords: acute kidney injury, levistolide A, TLR-4/NF-&Kgr;b, inflammatory response, antioxidant effect