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Gentamicin (GEN) is a kind of aminoglycoside antibiotic with the adverse effect of nephrotoxicity. Currently, no effective measures against the nephrotoxicity have been approved. In the present study, epigallocatechin gallate (EG), a useful ingredient in green tea, was used to attenuate its nephrotoxicity. EG was shown to largely attenuate the renal damage and the increase of malondialdehyde (MDA) and the decrease of glutathione (GSH) in GEN-injected rats. In NRK-52E cells, GEN increased the cellular ROS in the early treatment phase and ROS remained continuously high from 1.5 H to 24 H. Moreover, EG alleviated the increase of ROS and MDA and the decrease of GSH caused by GEN. Furthermore, EG activated the protein levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). After the treatment of GEN, the protein level of cleaved-caspase-3, the flow cytometry analysis and the JC-1 staining, the protein levels of glutathione peroxidase 4 (GPX4) and SLC7A11, were greatly changed, indicating the occurrence of both apoptosis and ferroptosis, whereas EG can reduce these changes. However, when Nrf2 was knocked down by siRNA, the above protective effects of EG were weakened. In summary, EG attenuated GEN-induced nephrotoxicity by suppressing apoptosis and ferroptosis. [ABSTRACT FROM AUTHOR]

Necroptosis is defined as a novel programmed cell necrosis that is mediated by receptor interacting serine–threonine protein kinase 1 (RIPK1) and other related signals. Necrosis, apoptosis and inflammation are commonly considered as the leading mechanism in acute kidney injury (AKI) induced by gentamicin (GEN), which is a useful antibiotic for treating the infection of Gram‐negative bacterial. However, the necroptosis in the pathogenesis of GEN‐induced AKI is unknown. In this study, to investigate the process and function of necroptosis in GEN‐induced AKI, NRK‐52E and HK‐2 cells and SD rats were used as the models. The necroptosis‐related proteins, including RIPK1, RIPK3, mixed lineage kinase domain‐like (MLKL) and phosphorylated MLKL (p‐MLKL), were all increasing time‐dependently when GEN was continuously given. By using the RIPK1 inhibitor necrostatin‐1 (NEC‐1) and RIPK3 inhibitor (CPD42), the GEN‐induced toxicity of tubular cells was alleviated. Moreover, it was validated that GEN‐induced cell apoptosis and inflammation were attenuated after treating with NEC‐1 or CPD42, both in vivo and in vitro. When MLKL was knocked down by siRNA, NEC‐1 and CPD42 can not further protect the damage of tubular cells by GEN. Although the using of pan‐caspase inhibitor Z‐VAD significantly decreased GEN‐induced apoptosis, it enhanced necroptosis and slightly promoted the decreased cell viability in GEN‐treated cells, with the protective effects weaker than NEC‐1 or CPD42. Finally, in vitro minimum inhibitory concentration (MIC) tests and bacteriostatic ring studies showed that NEC‐1 did not interfere with the antibiotic effects of GEN. Thus, suppressing necroptosis can serve as a promising strategy for the prevention of GEN‐induced nephrotoxicity. [ABSTRACT FROM AUTHOR]

Renal fibrosis, a common feature and leading cause for End Stage Renal Disease, still lacks effective therapy. In the current study, we detected and compared the anti-fibrotic effects of wogonin and wogonoside, two major components of Scutellaria baicalensis Georgi, in TGF-β1-treated tubular epithelial cells of human and murine origins. Results consistently showed that compared with wogonoside, wogonin inhibits TGF-β1-induced upregulated mRNA and protein levels of collagen I and α-SMA with more efficiency, which was further confirmed by the immunofluorescence results that wogonin decreased the percentage of collagen I and α-SMA positive cells in TGF-β1-treated tubular epithelial cells. Mechanistically, wogonin mainly decreased Smad3 phosphorylation, but had marginal effect on non-canonical TGF-β signaling pathways, such as p38 and ERK MAP Kinase. Furthermore, in the cells deficient for TGF-β signaling or downstream Smad3, results demonstrated that even high concentration of wogonin failed to further decrease the level of collagen I and α-SMA, indicating the essential role of TGF-β/Smad3 signaling inhibition in the therapeutic action of wogonin in TGF-β1-stimulated tubular epithelial cells. Collectively, our results indicated that wogonin may be utilized as a potential anti-fibrotic Traditional Chinese Medicine monomer in the treatment of renal fibrosis. [ABSTRACT FROM AUTHOR]