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

Abstract

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.

• Authors: Xiao-Ming Meng, Hai-Di Li, Wei-Feng Wu, Patrick Ming-Kuen Tang, Gui-Ling Ren, Li Gao, Xiao-Feng Li, Yang Yang, Tao Xu, Tao-Tao Ma, Zeng Li, Cheng Huang, Lei Zhang, Xiong-Wen Lv, Jun Li
• Journal: Laboratory investigation; a journal of technical methods and pathology (Lab Invest) Vol. 98 Issue 1 Pg. 79-94 (01 2018) ISSN: 1530-0307 [Electronic] United States
• PMID: 29200200 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Antineoplastic Agents
• Biomarkers
• Flavanones
• Protective Agents
• RIPK3 protein, human
• Receptor-Interacting Protein Serine-Threonine Kinases
• Ripk1 protein, mouse
• wogonin
• Cisplatin

Topics

• Acute Kidney Injury (chemically induced, metabolism, pathology, prevention & control)
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (chemistry, metabolism, pharmacology, therapeutic use)
• Antineoplastic Agents (adverse effects, chemistry, pharmacology)
• Apoptosis (drug effects)
• Binding Sites
• Biomarkers (blood, metabolism)
• Catalytic Domain
• Cell Line, Transformed
• Cell Line, Tumor
• Cisplatin (adverse effects, antagonists & inhibitors, pharmacology)
• Flavanones (chemistry, metabolism, pharmacology, therapeutic use)
• Humans
• Kidney (drug effects, immunology, metabolism, pathology)
• Kidney Tubules (drug effects, immunology, metabolism, ultrastructure)
• Macrophage Activation (drug effects)
• Male
• Mice, Inbred C57BL
• Microscopy, Electron, Transmission
• Molecular Docking Simulation
• Protective Agents (chemistry, metabolism, pharmacology, therapeutic use)
• RNA Interference
• Receptor-Interacting Protein Serine-Threonine Kinases (antagonists & inhibitors, chemistry, metabolism)