Salvianolate ameliorates renal tubular injury through the Keap1/Nrf2/ARE pathway in mouse kidney ischemia-reperfusion injury.

Acute kidney injury (AKI) is a common clinical disease characterized by rapid loss of renal function. Salvianolate is a prescribed Chinese medicine derived from traditional Chinese medicine Salvia miltiorrhiza bunge that possesses many pharmacological effects, the active components extracted from Salvia miltiorrhiza bunge have been proved to protect ischemia-reperfusion (I/R)-AKI. This study aims to validate the therapeutic effect of SAL on I/R-AKI, and explore its potential pharmacological mechanism. Mice were pretreated with/without salvianolate (10, 30, and 90 mg/kg) before renal ischemia-reperfusion operation. Serum creatinine, BUN, and H&E staining were performed to evaluate renal function. Immunofluorescence analysis was conducted to measure renal tubular injury including inflammatory factors and peroxide level. Apoptosis of the kidney tissues was determined by TUNEL assay. Keap1-Nrf2-ARE and apoptosis signaling pathways were measured by Western blot, RT-PCR, and YO-PRO-1 staining in kidneys or NRK52E cells. Pretreatment with SAL effectively alleviated renal function and ameliorated epithelial tubular injury, oxidative stress, and inflammatory response. Furthermore, the mechanistic study demonstrated that the SAL exerts anti-apoptotic effects through activation of the Keap1-Nrf2-ARE signaling pathway in renal tubular cells. These findings indicate the therapeutic benefit of salvianolate in the protection of renal injury from ischemia-reperfusion, and strengthen the evidence for the AKI treatment strategy by the anti-oxidative stress response, suggesting that SAL may be a potential agent for the treatment of AKI.

Sun D ，Cui S ，Ma H ，Zhu P ，Li N ，Zhang X ，Zhang L ，Xuan L ，Li J ... -  《-》

Urolithin A alleviates acute kidney injury induced by renal ischemia reperfusion through the p62-Keap1-Nrf2 signaling pathway.

Acute kidney injury (AKI) induced by renal ischemia reperfusion (RIR) is typically observed in renal surgeries and is a leading cause of renal failure. However, there is still an unmet medical need currently in terms of clinical treatments. Herein, we report the effect of Urolithin A (UA) in a mouse RIR model, wherein we demonstrated its underlying mechanism both in vitro and in vivo. The expression levels of p62 and Keap1 significantly decreased, while that of nuclear Nrf2 increased in vitro in a hypoxia cell model after UA treatment. Furthermore, the apoptosis of tubular cells was attenuated and the reactive oxygen species (ROS) levels were reduced in the kidneys in a mouse RIR model after UA administration. In this study, we demonstrated that UA can alleviate oxidative stress and promote autophagy by activating the p62-Keap1-Nrf2 signaling pathway, which could protect the kidneys from ischemia reperfusion injury.

Zhang Y ，Liu M ，Zhang Y ，Tian M ，Chen P ，Lan Y ，Zhou B ... -  《-》

Desflurane Preconditioning Protects Against Renal Ischemia-Reperfusion Injury and Inhibits Inflammation and Oxidative Stress in Rats Through Regulating the Nrf2-Keap1-ARE Signaling Pathway.

Kidney is sensitive to ischemia-reperfusion (I/R) injury because of its special structure and function. In this study, we aimed to explore the mechanism of desflurane (DFE) preconditioning effecting on renal I/R injury in rats. Renal I/R injury rats model was constructed, and the expressions of serum renal function parameters (blood urea nitrogen (BUN) and serum creatinine (SCr)) and lipid peroxidation-related factors were detected using corresponding commercial kits to assess the degrees of renal functional damage and oxidative stress. Hematoxylin--eosin (HE) staining and Masson trichrome staining were applied to measure the renal histologic damage. The expressions of inflammation-related factors were determined by ELISA assay. The cell apoptosis was analyzed using TUNEL, Western blot and immunohistochemistry (IHC). IHC was also used to detect the number of myeloperoxidase (MPO)-positive cells. The expressions of proteins associated with the Nrf2-Keap1-ARE pathway were assessed by Western blot and IHC. DFE preconditioning inhibited I/R injury-induced BUN and SCr increase and renal histologic injury in rats. Also, DFE suppressed the inflammation, apoptosis and oxidative stress caused by renal I/R injury in vivo. In addition, DFE preconditioning repressed peroxide-related factors (MDA, MPO and NO) expressions and promoted antioxidant-related factors (GSH, SOD, GPx and CAT) expressions. In addition, DFE promoted Nrf2-Keap1-ARE-related proteins including Nrf2, NQO1, HO-1, γ-GCS, GSR and GCLc expressions. DFE preconditioning protected the kidney as well as inhibited the inflammation, cell apoptosis and oxidative stress in renal I/R injury rats by activating the Nrf2-Keap1-ARE signaling pathway.

Zheng Y ，Lu H ，Huang H 《Drug Design Development and Therapy》

Loganin exerts a protective effect on ischemia-reperfusion-induced acute kidney injury by regulating JAK2/STAT3 and Nrf2/HO-1 signaling pathways.

To investigate the role of loganin in hypoxia/reperfusion (H/R)-induced renal tubular epithelial cells and ischemia/reperfusion-induced acute kidney injury (AKI). Cells were received H/R treatment and cultured with different concentrations of loganin. The cell activity and apoptosis were detected. The expressions of apoptosis-related proteins, inflammatory factors, oxidative stress related molecules, and related molecules of JAK2/STAT3 and Nrf2/HO-1 signaling pathways were measured. AKI model of mice was established by I/R procedure, and the kidney was collected for hematoxylin and eosin (HE) staining. H/R treatment inhibited cell activity and apoptosis, but loganin attenuated the effect of H/R. Moreover, loganin inhibited H/R-induced inflammatory response and oxidative stress in tubular epithelial cells. Loganin down-regulated the expression of apoptosis-related proteins, suppressed JAK2/STAT3 pathway, and activated Nrf2/HO-1 pathway. In animal experiment, loganin reduced tubular injury in AKI mice.Loganin had anti-apoptotic, anti-inflammatory, and anti-oxidative stress effects on H/R-induced tubular epithelial cells, and could improve AKI in mice induced by I/R. This effect might be achieved by inhibiting JAK2/STAT3 and activating the Nrf2/HO-1 signaling pathway.

Huang F ，Wang X ，Xiao G ，Xiao J ... -  《-》

Paeoniflorin alleviates hypoxia/reoxygenation injury in HK-2 cells by inhibiting apoptosis and repressing oxidative damage via Keap1/Nrf2/HO-1 pathway.

Acute kidney injury (AKI) is a serious disorder associated with significant morbidity and mortality. AKI and ischemia/reperfusion (hypoxia/reoxygenation, H/R) injury can be induced due to several reasons. Paeoniflorin (PF) is a traditional herbal medicine derived from Paeonia lactiflora Pall. It exerts diverse therapeutic effects, including anti-inflammatory, antioxidative, antiapoptotic, and immunomodulatory properties; thus, it is considered valuable for treating several diseases. However, the effects of PF on H/R injury-induced AKI remain unknown. In this study, we established an in vitro H/R model using COCL2 and investigated the functions and underlying mechanisms of PF on H/R injury in HK-2 cells. The cell vitality was evaluated using the cell count kit-8 assay. The DCFH-DA fluorescence probe was used to measure the levels of reactive oxygen species (ROS). Oxidative damage was detected using superoxide dismutase (SOD) and malondialdehyde (MDA) assay kits. Apoptotic relative protein and Keap1/Nrf2/HO-1 signaling were evaluated by Western blotting. Our results indicated that PF increased cell viability and SOD activity and decreased the ROS and MDA levels in HK-2 cells with H/R injury. PF inhibits apoptosis by increasing Bcl-2 and decreasing Bax. Furthermore, PF significantly upregulated the expression of HO-1 and Nrf2, but downregulated the expression of HIF-1α and Keap1. PF considerably increased Nrf2 nuclear translocation and unregulated the HO-1 expression. The Nrf2 inhibitor (ML385) could reverse the abovementioned protective effects of PF, suggesting that Nrf2 can be a critical target of PF. To conclude, we found that PF attenuates H/R injury-induced AKI by decreasing the oxidative damage via the Nrf2/HO-1 pathway and inhibiting apoptosis.

Xing D ，Ma Y ，Lu M ，Liu W ，Zhou H ... -  《BMC Nephrology》