1. Direct targeting of sEH with alisol B alleviated the apoptosis, inflammation, and oxidative stress in cisplatin-induced acute kidney injury
- Author
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Zhang, Juan, Luan, Zhi-Lin, Huo, Xiao-Kui, Zhang, Min, Morisseau, Christophe, Sun, Cheng-Peng, Hammock, Bruce D, and Ma, Xiao-Chi
- Subjects
Kidney Disease ,NF-E2-Related Factor 2 ,Renal and urogenital ,cisplatin ,Apoptosis ,soluble epoxide hydrolase ,Kidney ,Microbiology ,Applied Microbiology and Biotechnology ,Alisol B ,Humans ,2.1 Biological and endogenous factors ,Aetiology ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,Inflammation ,nephrotoxicity ,NF-kappa B ,Cell Biology ,Acute Kidney Injury ,Oxidative Stress ,5.1 Pharmaceuticals ,Medical Microbiology ,Tumor Suppressor Protein p53 ,Development of treatments and therapeutic interventions ,Other Biological Sciences ,Developmental Biology - Abstract
Acute kidney injury (AKI) is a pathological condition characterized by a rapid decrease in glomerular filtration rate and nitrogenous waste accumulation during hemodynamic regulation. Alisol B, from Alisma orientale, displays anti-tumor, anti-complement, and anti-inflammatory effects. However, its effect and action mechanism on AKI is still unclear. Herein, alisol B significantly attenuated cisplatin (Cis)-induced renal tubular apoptosis through decreasing expressions levels of cleaved-caspase 3 and cleaved-PARP and the ratio of Bax/Bcl-2 depended on the p53 pathway. Alisol B also alleviated Cis-induced inflammatory response (e.g. the increase of ICAM-1, MCP-1, COX-2, iNOS, IL-6, and TNF-α) and oxidative stress (e.g. the decrease of SOD and GSH, the decrease of HO-1, GCLC, GCLM, and NQO-1) through the NF-κB and Nrf2 pathways. In a target fishing experiment, alisol B bound to soluble epoxide hydrolase (sEH) as a direct cellular target through the hydrogen bond with Gln384, which was further supported by inhibition kinetics and surface plasmon resonance (equilibrium dissociation constant, K D = 1.32 μM). Notably, alisol B enhanced levels of epoxyeicosatrienoic acids and decreased levels of dihydroxyeicosatrienoic acids, indicating that alisol B reduced the sEH activity in vivo. In addition, sEH genetic deletion alleviated Cis-induced AKI and abolished the protective effect of alisol B in Cis-induced AKI as well. These findings indicated that alisol B targeted sEH to alleviate Cis-induced AKI via GSK3β-mediated p53, NF-κB, and Nrf2 signaling pathways and could be used as a potential therapeutic agent in the treatment of AKI.
- Published
- 2023