Ischemia/reperfusion injury (I/R) is one of the leading causes of acute kidney injury (AKI) that typically occurs in renal surgeries. However, renal I/R still currently lacks effective therapeutic targets. In this study, we proved that inhibition of Brd4 with its selective inhibitor, JQ1, could exert a protective role in renal I/R injury in mice. Inhibiting Brd4 with either JQ1 or genetic knockdown resulted in reduction of endoplasmic reticulum stress (ERS)-associated protein and proapoptotic protein expression both in I/R-induced injury and hypoxia/reoxygenation (H/R) stimulation in HK-2 cells. H/R-induced apoptosis and ERS depended on oxidative stress in vitro. Moreover, FoxO4, which is involved in the generation of hydrogen peroxide, was up-regulated during H/R stimulation-mediated apoptosis and ERS, and this upregulation could be abolished by Brd4 inhibition. Consistently, FoxO4-mediated ROS generation was attenuated upon inhibition of Brd4 with JQ1 or siRNA against Brd4. Further, the transcriptional activity of FoxO4 was suppressed by PI3K and AKT phosphorylation, which are upstream signals of FoxO4 expression, and were enhanced by Brd4 both in vivo and in vitro. In conclusion, our results proved that Brd4 inhibition blocked renal apoptotic and ERS protein expression by preventing FoxO4-dependent ROS generation through the PI3K/AKT pathway, indicating that Brd4 could be a potential therapeutic target for renal I/R injury.

Oxidative stress is a key component of renal ischemia/reperfusion (I/R) injury. Fucoxanthin (Fx), a marine carotenoid with enhanced antioxidant capacity, acts as a ROS inhibitor in diseases such as ischemic stroke and acute lung injury. We hypothesized that fucoxanthin could attenuate renal I/R‐induced oxidative damage. C57BL/6 mice (n = 30) were randomly assigned to sham, IR, IR + DMSO, and IR + Fx (25, 50, and 100 mg/kg) groups. The renal I/R injury was induced by clamping the left kidney nephron tip in mice. Fucoxanthin was injected intraperitoneally 24 hours before surgery. Compared with the IR group, pretreatment with fucoxanthin significantly improved renal dysfunction and tissue structural damage and inhibited ROS levels and apoptosis. Consistent results were observed in HK‐2 cells. Besides, we found that renal I/R resulted in decreased expression of Sirt1, Nrf2, and HO‐1, while fucoxanthin upregulated the expression of Sirt1, Nrf2, and HO‐1. The protective effects of fucoxanthin were significantly reversed by EX527 (a selective inhibitor of Sirt1) or si‐Sirt1. In conclusion, our study investigated the protective effect of fucoxanthin against renal I/R injury, and the underlying mechanism may be related to the activation of the Sirt1/Nrf2/HO‐1 signaling pathway by fucoxanthin to attenuate oxidative stress‐induced apoptosis.

Diabetic patients are more susceptible to renal ischemia/reperfusion (I/R) injury (RI/RI) and have a poor prognosis, but the underlying mechanism remains unclear. The present study aimed to examine whether diabetes could worsen acute kidney injury induced by I/R in rats and clarify its mechanism. Control and streptozotocin-induced diabetic rats were subjected to 45 min renal pedicle occlusion followed by 24 h reperfusion. Tert-butylhydroquinone (TBHQ, 16.7 mg/kg) was administrated intraperitoneally 3 times at intervals of 8 h before ischemia. Serum and kidneys were harvested after reperfusion to evaluate renal function and histological injury. Enzyme-linked immunosorbent assays were used to test pro-inflammatory cytokines. Terminal deoxynucleotidyl-transferase-mediated dUTP nick-end labeling assays were used to detect apoptotic cells, and western blotting was performed to determine the expression of B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), and cleaved caspase-3, as well as oxidative stress and inflammation-related proteins, such as nuclear factor-erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), Toll-like receptor 4 (TLR4), and nuclear factor-κB (NF-κB). Compared with control animals, diabetic rats undergoing I/R exhibited more severe tubular damage and renal dysfunction. Diabetes exacerbated oxidative stress, the inflammatory response, and apoptosis after renal I/R by enhancing TLR4/NF-κB signaling and blocking the Nrf2/HO-1 pathway. RI/RI in diabetic rats was attenuated by pretreatment with TBHQ (a Nrf2 agonist), which exerted anti-inflammatory and anti-apoptotic properties by inhibiting NF-κB signaling. These findings indicate that hyperglycemia exacerbates RI/RI by intensifying oxidative stress, inflammation, and apoptosis. Antioxidant pretreatment may alleviate RI/RI in diabetic patients.

Endoplasmic reticulum (ER) stress, pyroptosis, and apoptosis are critical molecular events in the occurrence and progress of renal ischemia reperfusion (I/R) injury. Naringenin (4′,5,7‐trihydroxyflavanone) is one of the most widely consumed flavonoids with powerful antioxidant and anti‐inflammatory activities. However, whether naringenin is able to relieve renal I/R injury and corresponding mechanisms have not been fully clarified. This study was aimed at exploring its role and relevant mechanisms in renal I/R injury. The C57Bl/6 mice were randomly assigned to receive administration with naringenin (50 mg/kg/d) or sterile saline (1.0 mL/d) for 3 d by gavage and suffered from renal I/R surgery. One specific ER stress inhibitor, 4‐phenylbutyric acid (4‐PBA, 100 mg/kg/d), was intraperitoneally administered to validate the regulation of ER stress on pyroptosis and apoptosis. Cultured HK‐2 cells went through the process of hypoxia/reoxygenation (H/R) to perform cellular experiments with the incubation of naringenin (200 μM), 4‐PBA (5 mM), or brusatol (400 nM). The animal results verified that naringenin obviously relieved renal I/R injury, while it refined renal function and attenuated tissue structural damage. Furthermore, naringenin treatment inhibited I/R‐induced ER stress as well as pyroptosis and apoptosis as indicated by decreased levels of specific biomarkers such as GRP78, CHOP, caspase‐12, NLRP3, ASC, caspase‐11, caspase‐4, caspase‐1, IL‐1β, GSDMD‐N, BAX, and cleaved caspase‐3 in animals and HK‐2 cells. Besides, the upregulated expression of Nrf2 and HO‐1 proteins after naringenin treatment suggested that naringenin activated the Nrf2/HO‐1 signaling pathway, which was again authenticated by the usage of brusatol (Bru), one unique inhibitor of the Nrf2 pathway. Importantly, the application of 4‐PBA showed that renal I/R‐generated pyroptosis and apoptosis were able to be regulated by ER stress in vivo and in vitro. In conclusion, naringenin suppressed ER stress by activating Nrf2/HO‐1 signaling pathway and further alleviated pyroptosis and apoptosis to protect renal against I/R injury.

Disulfidptosis is a newly discovered mode of cell death induced by disulfide stress. However, the prognostic value of disulfidptosis-related genes (DRGs) in renal cell carcinoma (RCC) remains to be further elucidated. In this study, consistent cluster analysis was used to classify 571 RCC samples into three DRG-related subtypes based on changes in DRGs expression. Through univariate regression analysis and LASSO-Cox regression analysis of differentially expressed genes (DEGs) among three subtypes, we constructed and validated a DRG risk score to predict the prognosis of patients with RCC, while also identifying three gene subtypes. Analysis of DRG risk score, clinical characteristics, tumor microenvironment (TME), somatic cell mutations, and immunotherapy sensitivity revealed significant correlations between them. A series of studies have shown that MSH3 can be a potential biomarker of RCC, and its low expression is associated with poor prognosis in patients with RCC. Last but not least, overexpression of MSH3 promotes cell death in two RCC cell lines under glucose starvation conditions, indicating that MSH3 is a key gene in the process of cell disulfidptosis. In summary, we identify potential mechanism of RCC progression through DRGs -related tumor microenvironment remodeling. In addition, this study has successfully established a new disulfidptosis-related genes prediction model and discovered a key gene MSH3. They may be new prognostic biomarkers for RCC patients, provide new insights for the treatment of RCC patients, and may inspire new methods for the diagnosis and treatment of RCC patients.

Renal cell carcinoma is particularly sensitive to ferroptosis, an iron-dependent non-apoptotic form of cell death. This mechanism does not require activation of caspase or the participation of other apoptotic effector molecules (such as BAX or BAK), nor is it accompanied by the morphological characteristics or biochemical processes of apoptosis. The STEAP3 gene was found because it promotes tumor apoptosis in prostate cancer, but its role in renal cell carcinoma has not been studied in depth. Through real-time quantitative polymerase chain reaction, we found that the expression of the STEAP3 gene was upregulated in renal cell carcinoma tissue samples and cell lines, and it was found to be highly expressed in renal cell carcinoma tissue through immunohistochemistry. This upregulation is related to poor survival and prognosis of patients. We used erastin, a ferroptosis inducer, found that renal cell carcinoma became more susceptible to ferroptosis after knocking down STEAP3. The results indicate that renal cell carcinoma cell lines with knocked down STEAP3 expression are more sensitive to ferroptosis, and this effect occurs through the p53/xCT pathway. In summary, our research helps to identify new biomarkers and provides new targets for the treatment of renal cell carcinoma.