Background. Extensive evidence has demonstrated that oxidative stress, pyroptosis, and proinflammatory programmed cell death are related to renal ischemia/reperfusion (I/R) injury. However, the underlying mechanism remains to be illustrated. Protein arginine methylation transferase 5 (PRMT5), which mediates arginine methylation involved in the regulation of epigenetics, exhibits a variety of biological functions and essential roles in diseases. The present study investigated the role of PRMT5 in oxidative stress and pyroptosis induced by I/R injury in a mouse model and in a hypoxia/reoxygenation (H/R) model of HK-2 cells. Methods. C57 mice were used as an animal model. All mice underwent right nephrectomy, and the left renal pedicles were either clamped or not. Renal I/R injury was induced by ligating the left renal pedicle for 30 min followed by reperfusion for 24 h. HK-2 cells were exposed to normal conditions or stimulation through H/R. EPZ015666(EPZ)—a selective potent chemical inhibitor—and small interfering RNA (siRNA) were administered to suppress the function and expression of PRMT5. The levels of urea nitrogen and creatinine in the serum and renal tissue injury were assessed. Immunohistochemistry, western blotting, and reverse transcription-polymerase chain reaction were used to evaluate pyroptosis-related proteins including nod-like receptor protein-3, ASC, caspase-1, caspase-11, GSDMD-N, and interleukin-1β. Cell apoptosis and cell viability were detected through flow cytometry, and the levels of reactive oxygen species (ROS) and hydrogen peroxide (H₂O₂) were measured. Ki-67 was used to assess the proliferation of renal tubular epithelium. In addition, the activity of malondialdehyde and superoxide dismutase was determined. Results. I/R or H/R induced an increase in the expression of PRMT5. Inhibition of PRMT5 by EPZ alleviated oxidative stress and I/R- or H/R-induced pyroptosis. In renal tissue, the application of EPZ promoted the proliferation of tubular epithelium. In addition, H/R-induced pyroptosis in HK-2 cells was dependent on oxidative stress in vitro. Administration of either EPZ or siRNA led to decreased expression of pyroptosis-related proteins. Inhibition of PRMT5 also attenuated the I/R- or H/R-induced oxidative stress in vivo and in HK-2 cells, respectively. It also resulted in a distinct decrease in the levels of malondialdehyde and H₂O₂, and an apparent increase in superoxide dismutase activity in mouse renal tissue. Moreover, it led to a significant decrease in the levels of ROS and H₂O₂ in HK-2 cells. When activated, NF-E2-related factor/heme oxygenase-1 (Nrf2/HO-1)—a key regulator of various cytoprotective proteins that withstand oxidative damage—can decrease the generation of ROS. Nrf2/HO-1 was downregulated during I/R in tissues and H/R in HK-2 cells, and this effect was reversed by the PRMT5 inhibitor. Furthermore, the expressions of Nrf2 and HO-1 proteins were markedly upregulated by EPZ or siRNA against PRMT5. Conclusion. PRMT5 is involved in ischemia- and hypoxia-induced oxidative stress and pyroptosis in vitro and in vivo. Inhibition of PRMT5 may ameliorate renal I/R injury by suppressing oxidative stress and pyroptosis via the activation of the Nrf2/HO-1 pathway, as well as promoting the proliferation of tubular epithelium. Therefore, PRMT5 may be a promising therapeutic target.

Ischemia–reperfusion (I/R) is a common pathological phenomenon that occurs in numerous organs and diseases. It generally results from secondary damage caused by the recovery of blood flow and reoxygenation, followed by ischemia of organ tissues, which is often accompanied by severe cellular damage and death. Currently, effective treatments for I/R injury (IRI) are limited. Ferroptosis, a new type of regulated cell death (RCD), is characterized by iron overload and iron-dependent lipid peroxidation. Mounting evidence has indicated a close relationship between ferroptosis and IRI. Ferroptosis plays a significantly detrimental role in the progression of IRI, and targeting ferroptosis may be a promising approach for treatment of IRI. Considering the substantial progress made in the study of ferroptosis in IRI, in this review, we summarize the pathological mechanisms and therapeutic targets of ferroptosis in IRI.

The mitogen-activated protein kinase signaling pathway can be activated by a variety of growth factors, cytokines, and hormones, and mediates numerous intracellular signals related to cellular activities, including cell proliferation, motility, and differentiation. It has been widely studied in the occurrence and development of inflammation and tumor. Hepatic ischemia-reperfusion injury (HIRI) is a common pathophysiological phenomenon that occurs in surgical procedures such as lobectomy and liver transplantation, which is characterized by severe inflammatory reaction after ischemia and reperfusion. In this review, we mainly discuss the role of p38, ERK1/2, JNK in MAPK family and TAK1 and ASK1 in MAPKKK family in HIRI, and try to find an effective treatment for HIRI.

Renal ischemia-reperfusion (I/R) injury is an inevitable complication during renal transplantation and is closely related to patient prognosis. Mitochondrial damage induced oxidative stress is the core link of renal I/R injury. Ligustilide (LIG), a natural compound extracted from ligusticum chuanxiong hort and angelica sinensis, has exhibited the potential to protect mitochondrial function. However, whether LIG can ameliorate renal I/R injury requires further investigation. Delving deeper into the precise targets and mechanisms of LIG's effect on renal I/R injury is crucial. This study aimed to elucidate the specific mechanism of LIG's protective effect on renal I/R injury. In this study, an in vivo model of renal ischemia-reperfusion (I/R) injury was developed in mice, along with an in vitro model of hypoxia-reoxygenation (H/R) using human proximal renal tubular epithelial cells (HK-2). To assess the impact of LIG on renal injury, various methods were employed, including serum creatinine (Cr) and blood urea nitrogen (BUN) testing, hematoxylin and eosin (HE) staining, and immunohistochemistry (IHC) for kidney injury molecule-1 (KIM-1). The effects of LIG on oxidative stress were examined using fluorescent probes dihydroethidium (DHE) and dichlorodihydrofluorescein diacetate (DCFH-DA), TdT-mediated dUTP Nick-End Labeling (TUNEL) staining, and flow cytometry. Additionally, the influence of LIG on mitochondrial morphology and function was evaluated through transmission electron microscopy (TEM), Mito Tracker Red CMXRos staining, adenosine triphosphate (ATP) concentration assays, and JC-1 staining. The potential mechanism involving LIG and Sirt3 was explored by manipulating Sirt3 expression through cell transfection. The results showed that LIG could provide protective function for mitochondria to alleviate oxidative stress induced by renal I/R. Further mechanistic studies indicated that LIG maintained mitochondrial homeostasis by targeting Sirt3. Our findings demonstrated that LIG alleviated oxidative stress during renal I/R injury through maintaining Sirt3-dependent mitochondrial homeostasis. Overall, our data raised the possibility of LIG as a novel therapy for renal I/R injury.