Effects and molecular mechanism of pachymic acid on ferroptosis in renal ischemia reperfusion injury

Abstract

Acute kidney injury (AKI) is a common clinical disease. Ferropotosis, a new type of regulatory cell death, serves an important regulatory role in AKI. Pachymic acid (PA), a lanostane-type triterpenoid from Poria cocos, has been reported to be protective against AKI. However, the protective mechanism of PA in AKI is not yet fully understood. The present study aimed to investigate the effect and molecular mechanism of PA on ferroptosis in renal ischemia reperfusion injury in vivo. A total of 30 mice were intraperitoneally injected with 5, 10 and 20 mg/kg PA for 3 days. A bilateral renal pedicle clip was used for 40 min to induce renal ischemia-reperfusion injury and establish the model. The results demonstrated that treatment with PA decreased serum creatinine and blood urea nitrogen, and ameliorated renal pathological damage. Transmission electron microscopy revealed no characteristic changes in ferroptosis in the mitochondria of the renal tissue in the high-dose PA group, and only mild edema. Furthermore, treatment with PA increased glutathione expression, and decreased the expression levels of malondialdehyde and cyclooxygenase 2. Treatment with PA enhanced the protein and mRNA expression levels of the ferroptosis related proteins, glutathione peroxidase 4 (GPX4), solute carrier family 7 (cationic amino acid transporter, y+ system) member 11 (SLC7A11) and heme oxygenase 1 (HO-1) in the kidney, and increased the expression levels of nuclear factor erythroid derived 2 like 2 (NRF2) signaling pathway members. Taken together, the results of the present study suggest that PA has a protective effect on ischemia-reperfusion induced acute kidney injury in mice, which may be associated with the inhibition of ferroptosis in the kidneys through direct or indirect activation of NRF2, and upregulation of the expression of the downstream ferroptosis related proteins, GPX4, SLC7A11 and HO-1.

Targeting Ferroptosis: Pathological Mechanism and Treatment of Ischemia‐Reperfusion Injury

“…According to research, under the treatment of pachymic acid, the renal function of mice with renal I/R injury can be improved, and renal injury can be alleviated. The protective effect of pachymic acid may be related to the inhibition of renal ferroptosis through directly or indirectly activating Nrf2 and upregulating downstream GPX4, system x c − , and HO-1 [ 110 ]. Additionally, XJB-5-131 is a mitochondrial-targeted nitroxide with a high affinity for tubular epithelial cells [ 111 ].…”

Synergistic effects of methyl 2-cyano-3,11-dioxo-18beta-olean-1,-12-dien-30-oate and erlotinib on erlotinib-resistant non-small cell lung cancer cells

“…The second synergistic effect of ERL + CDODA-Me was indicative of oxidative stress events such as ferroptosis, which is typically associated with the upregulation or downregulation of iron-related transcripts, such as heme oxygenase-1 [ 54 , 55 ], ferritin heavy chain 1 (FTH1) [ 56 ], transferrin receptor 1, ferroportin, and altered expression of glutathione-related genes such as cystine/glutamate transporter xc(-) (SLC7A11), glutathione peroxidase 4 (GPX4), and glutamate-cysteine ligase, which are regulated by Nrf2 transcription in response to oxidative stress. ERL + CDODA-Me results in upregulation in Nrf2, similar to that observed as a survival response triggered by the presence of oxidative dangers by elevating intracellular glutathione-related antioxidant systems [ 57 ]. Drugs that act as iron chelators or ferroptosis inhibitors [ 58 , 59 ] can inhibit cell death, while inhibition of cysteine uptake, attenuation of glutathione transferases, or inactivation of GPX4 can exacerbate it [ 60 ].…”

CIRBP promotes ferroptosis by interacting with ELAVL1 and activating ferritinophagy during renal ischaemia‐reperfusion injury

“…Similarly, we found that levels of GSH were higher when either CIRBP or ELAVL1 were suppressed and lower when ferroptosis was increased. Recently, Jiang et al 40 found that pachymic acid increased levels of GSH expression and lowered ferroptosis in a murine model of IR. They proposed that a possible mechanism could be through the activation of NRF2.…”