Protective effect of inhibiting necroptosis on gentamicin‐induced nephrotoxicity

Hu, Bingfeng; Gong, Qian; Chen, Shi‐qing; Yue, Lin; Ma, Wen‐xian; Wang, Fang; Feng, Xiaowen; Wang, Jia‐nan; Li, Chao; Liu, Ming‐ming; Wang, Xue‐fu; Meng, Xiao‐Ming; Li, Jun; Wen, Jiagen

doi:10.1096/fj.202200163r

Cited by 7 publications

(5 citation statements)

References 46 publications

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“…Nec-1 is an inhibitor of receptor-interacting protein 1 kinase, which inhibits RIPK1 kinase activity and reduces LN inflammation [ 36 , 37 ]. As shown in Figure 4 C, PMA can promote NET production.…”

Section: Resultsmentioning

confidence: 99%

Multifunctional Polydopamine-Based Nanoparticles for Dual-Mode Imaging Guided Targeted Therapy of Lupus Nephritis

Wang

Han

et al. 2022

Pharmaceutics

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Lupus nephritis (LN) is a common and refractory inflammation of the kidneys caused by systemic lupus erythematosus. Diagnosis and therapies at this stage are inefficient or have severe side effects. In recent years, nanomedicines show great potential for imaging diagnosis and controlled drug release. Herein, we developed a polydopamine (PDA)-based nanocarrier modified with Fe3O4 and Pt nanoparticles and loaded with necrostatin-1 (Nec-1) for the bimodal imaging and therapy of LN. Results demonstrate that Nec-1/PDA@Pt-Fe3O4 nanocarrier exhibits good biocompatibility. Nec-1, as an inhibitor of receptor-interacting protein 1 kinase, can be used to inhibit receptor-interacting protein 1 kinase activity and then reduces inflammation due to LN. Experiments in vitro and in the LN mouse model confirmed that the nanocarrier can reduce neutrophil extracellular traps (NETs) production by RIPK1 and alleviate the progression of inflammation. Previous studies proved that Pt nanoparticles can catalyze H2O2 to produce oxygen. A blood oxygen graph of mouse photoacoustic tomography confirmed that Nec-1/PDA@Pt-Fe3O4 can generate oxygen to fight against the hypoxic microenvironment of LN. PDA and Fe3O4 are used as photographic developers for photoacoustic or magnetic resonance imaging. The preliminary imaging results support Nec-1/PDA@Pt-Fe3O4 potential for photoacoustic/magnetic resonance dual-mode imaging, which can accurately and non-invasively monitor microscopic changes due to diseases. Nec-1/PDA@Pt-Fe3O4 combining these advantages exhibited outstanding performance in LN imaging and therapy. This work offers valuable insights into LN diagnosis and therapy.

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Section: Resultsmentioning

confidence: 99%

Multifunctional Polydopamine-Based Nanoparticles for Dual-Mode Imaging Guided Targeted Therapy of Lupus Nephritis

Wang

Han

et al. 2022

Pharmaceutics

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“…Compared with that reported in our previous study, the current study was performed in two more typical and common AKI models. Our study focused on the specific mechanism and site of action of RIPK3 in the necrosis pathway in the AKI models, whereas the previous study had demonstrated the effectiveness of Cpd‐42 in various AKI models from a different aspect (Hu et al, 2022). In this study, we used two in vitro models—cisplatin‐ and H/R‐induced renal cell injury—to determine whether Cpd‐42 exerts renoprotective effects.…”

Section: Discussionmentioning

confidence: 99%

Compound‐42 alleviates acute kidney injury by targeting RIPK3‐mediated necroptosis

Wang

Suo

et al. 2023

British J Pharmacology

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Background and PurposeNecroptosis plays an essential role in acute kidney injury and is mediated by receptor‐interacting protein kinase 1 (RIPK1), receptor‐interacting protein kinase 3 (RIPK3), and mixed lineage kinase domain‐like pseudokinase (MLKL). A novel RIPK3 inhibitor, compound 42 (Cpd‐42) alleviates the systemic inflammatory response. The current study was designed to investigate whether Cpd‐42 exhibits protective effects on acute kidney injury and reveal the underlying mechanisms.Experimental ApproachThe effects of Cpd‐42 were determined in vivo through cisplatin‐ and ischaemia/reperfusion (I/R)‐induced acute kidney injury and in vitro through cisplatin‐ and hypoxia/re‐oxygenation (H/R)‐induced cell damage. Transmission electron microscopy and periodic acid–Schiff staining were used to identify renal pathology. Cellular thermal shift assay and RIPK3‐knockout mouse renal tubule epithelial cells were used to explore the relationship between Cpd‐42 and RIPK3. Molecular docking and site‐directed mutagenesis were used to determine the binding site of RIPK3 with Cpd‐42.Key ResultsCpd‐42 reduced human proximal tubule epithelial cell line (HK‐2) cell damage, necroptosis and inflammatory responses in vitro. Furthermore, in vivo, cisplatin‐ and I/R‐induced acute kidney injury was alleviated by Cpd‐42 treatment. Cpd‐42 inhibited necroptosis by interacting with two key hydrogen bonds of RIPK3 at Thr94 and Ser146, which further blocked the phosphorylation of RIPK3 and mitigated acute kidney injury.Conclusion and ImplicationsActing as a novel RIPK3 inhibitor, Cpd‐42 reduced kidney damage, inflammatory response and necroptosis in acute kidney injury by binding to sites Thr94 and Ser146 on RIPK3. Cpd‐42 could be a promising treatment for acute kidney injury.

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“…The GEN group was added with different concentrations of GEN (0, 0.5, 1, 2, 4, 8, 16, 32, and 64 mM) and the GEN + EG group added the same concentrations of GEN and EG (25 μM). Finally, the turbidity of the two groups was compared after incubation for 24 H at 37 °C [ 39 ].…”

Section: Methodsmentioning

confidence: 99%

Epigallocatechin Gallate Attenuates Gentamicin-Induced Nephrotoxicity by Suppressing Apoptosis and Ferroptosis

Yue

Yang

et al. 2022

Molecules

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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.

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Protective effect of inhibiting necroptosis on gentamicin‐induced nephrotoxicity

Cited by 7 publications

References 46 publications

Multifunctional Polydopamine-Based Nanoparticles for Dual-Mode Imaging Guided Targeted Therapy of Lupus Nephritis

Multifunctional Polydopamine-Based Nanoparticles for Dual-Mode Imaging Guided Targeted Therapy of Lupus Nephritis

Compound‐42 alleviates acute kidney injury by targeting RIPK3‐mediated necroptosis

Epigallocatechin Gallate Attenuates Gentamicin-Induced Nephrotoxicity by Suppressing Apoptosis and Ferroptosis

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