Wogonin protects against cisplatin-induced acute kidney injury by targeting RIPK1-mediated necroptosis

• Published in: Laboratory investigation Vol. 98; no. 1; pp. 79 - 94
• Main Authors: Meng, Xiao-Ming, Li, Hai-Di, Wu, Wei-Feng, Ming-Kuen Tang, Patrick, Ren, Gui-Ling, Gao, Li, Li, Xiao-Feng, Yang, Yang, Xu, Tao, Ma, Tao-Tao, Li, Zeng, Huang, Cheng, Zhang, Lei, Lv, Xiong-Wen, Li, Jun
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.01.2018; Nature Publishing Group US; Nature Publishing Group
• Subjects: 13/1; 13/21; 13/31; 13/51; 13/89; 14/28; 38/77; 42/89; 45/90; 631/337/470; 64/60; 692/699/1585/4; 82/51; 82/83; 96/31; Acute Kidney Injury - chemically induced; Acute Kidney Injury - metabolism; Acute Kidney Injury - pathology; Acute Kidney Injury - prevention & control; Animals; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - metabolism; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Antineoplastic Agents - adverse effects; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Binding Sites; Biomarkers - blood; Biomarkers - metabolism; Catalytic Domain; Cell Line, Transformed; Cell Line, Tumor; Chemotherapy; Cisplatin; Cisplatin - adverse effects; Cisplatin - antagonists & inhibitors; Cisplatin - pharmacology; Creatinine; Electron microscopy; Flavanones - chemistry; Flavanones - metabolism; Flavanones - pharmacology; Flavanones - therapeutic use; Hepatoma; Humans; Infiltration; Inflammation; Injuries; Kidney - drug effects; Kidney - immunology; Kidney - metabolism; Kidney - pathology; Kidney Tubules - drug effects; Kidney Tubules - immunology; Kidney Tubules - metabolism; Kidney Tubules - ultrastructure; Kidneys; Laboratory Medicine; Macrophage Activation - drug effects; Macrophages; Male; Medicine; Medicine & Public Health; Mice, Inbred C57BL; Microscopy, Electron, Transmission; Molecular docking; Molecular Docking Simulation; Necroptosis; NF-κB protein; Pathology; Protective Agents - chemistry; Protective Agents - metabolism; Protective Agents - pharmacology; Protective Agents - therapeutic use; Receptor-Interacting Protein Serine-Threonine Kinases - antagonists & inhibitors; Receptor-Interacting Protein Serine-Threonine Kinases - chemistry; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism; research-article; RNA Interference; Rodents; Therapy; Urea
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1038/labinvest.2017.115

Acute kidney injury (AKI), characterized by aggressive inflammatory responses and destruction of renal resident cells, can cause abrupt kidney dysfunction. To date, effective therapy for AKI is lacking. In this study, we evaluated the renoprotective effect of wogonin, an herbal active compound, using a cisplatin-induced AKI mouse model. In vivo results show that wogonin substantially suppressed the increased levels of serum creatinine and blood urea nitrogen (BUN) almost to the normal level. Wogonin also attenuated tubular damage, shown by PAS staining, electron microscopy and molecular analysis of KIM-1. In addition, wogonin suppressed kidney inflammation as indicated by a >60% decrease in macrophage infiltration, a >50% reduction in inflammatory cytokine production and inhibited NF-κB activation in the injured kidney. Mechanistically, molecular docking results show that wogonin effectively inhibited RIPK1 by occupying the ATP-binding pocket of the enzyme, which is a key regulator of necroptosis. Moreover, inhibition of RIPK1, or RIPK3, reversed the protective effects of wogonin in cisplatin-treated HK2 cells, indicating wogonin works in a RIPK1/RIPK3-dependent manner. Surprisingly, wogonin enhanced the anti-proliferative effect of cisplatin on human hepatoma HepG2 cells. Thus, our findings suggest wogonin may be a renoprotective adjuvant for cisplatin-based anticancer therapy.