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, KD = 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.

Surface‐Engineered Vanadium Carbide MXenzyme for Anti‐Inflammation and Photoenhanced Antitumor Therapy of Colon Diseases

“…Besides, Cleaved Poly Adp Ribose Polymerase (PARP) and Cleaved CASPASE3 are used as markers of cell apoptosis. [ 30 ] We found that H 2 O 2 treatment caused a remarkable increase in Cleaved‐PARP and Cleaved‐CASPASE3, and Ga/V 2 C‐NH 2 treatment reduced Cleaved‐PARP and Cleaved‐CASPASE3 level. These data indicated that Ga/V 2 C‐NH 2 relieved inflammation‐induced apoptosis in HUVECs and NCM460 (Figure 3D).…”

Agrimol B alleviates cisplatin-induced acute kidney injury by activating the Sirt1/Nrf2 signaling pathway in mice

“…Oxidative stress is one of the most critical factors in CDDP-induced AKI, followed by ROS accumulation [15] . Oxidative stress can promote histopathological lesions by increasing the production of lipid peroxidation products and decreasing the levels of antioxidant enzymes [ 26 , 27 ]. Excessive ROS accumulation can cause oxidation of lipids, proteins and DNA and activate multiple signaling pathways [23] .…”

Regulation of soluble epoxide hydrolase in renal-associated diseases: insights from potential mechanisms to clinical researches

“…Furthermore, more EET is released when intracellular phospholipids are hydrolyzed, maintaining the increased intracellular concentration of unesterified EET ( 15 ). Numerous researches have shown that either the genetic deletion or pharmacological inhibition of sEH can decrease blood pressure ( 24 ), suppress inflammatory response ( 5 ), attenuate histological damage, and alleviate the progression of renal tubulointerstitial fibrosis in diabetic nephropathy, hypertensive nephropathy, and unilateral ureteral obstruction models ( 6 , 22 , 23 ). Due to its potential role in kidney diseases, sEH is being pursued as a potential pharmacological target.…”