Direct targeting of sEH with alisol B alleviated the apoptosis, inflammation, and oxidative stress in cisplatin-induced acute kidney injury.

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.

• Authors: Juan Zhang, Zhi-Lin Luan, Xiao-Kui Huo, Min Zhang, Christophe Morisseau, Cheng-Peng Sun, Bruce D Hammock, Xiao-Chi Ma
• Journal: International journal of biological sciences (Int J Biol Sci) Vol. 19 Issue 1 Pg. 294-310 ( 2023) ISSN: 1449-2288 [Electronic] Australia
• PMID: 36594097 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The author(s).

Chemical References

• Cisplatin
• alisol B
• NF-kappa B
• NF-E2-Related Factor 2
• Tumor Suppressor Protein p53

Topics

• Humans
• Cisplatin (toxicity)
• NF-kappa B (metabolism)
• NF-E2-Related Factor 2 (metabolism)
• Tumor Suppressor Protein p53 (metabolism)
• Acute Kidney Injury (chemically induced, drug therapy, metabolism)
• Apoptosis
• Kidney (metabolism)
• Oxidative Stress
• Inflammation (drug therapy, metabolism)