NADPH oxidase 4 promotes cisplatin-induced acute kidney injury via ROS-mediated programmed cell death and inflammation.

Abstract

The goal of this study was to elucidate the functional role of Nox4 during acute kidney injury (AKI). NADPH oxidases are a major source of reactive oxygen species (ROS) in the kidney in normal and pathological conditions. Among NADPH oxidase isoforms, NADPH oxidase4 (Nox4) is highly expressed in the kidney and has an important role in kidney diseases, such as diabetic nephropathy and renal carcinoma. We previously found that Nox4 expression significantly increased in the toxic AKI model. However, its functional role and mechanism of action in AKI are still unknown. We scavenged ROS with apocynin in vitro and in vivo and found it attenuated cisplatin-triggered renal function decline. It also alleviated programmed cell death and renal inflammation, indicating a critical role for ROS in mediating AKI. Nox4 protein and mRNA levels were substantially upregulated by cisplatin in vivo and in vitro. Nox4 knockdown alleviated cisplatin-induced cell death and inflammatory response, while Nox4 overexpression aggravated them. Moreover, N-acetyl-L-cysteine (NAC)-mediated inhibition of ROS suppressed cell injury led by Nox4 overexpression, indicating Nox4-mediated ROS generation may be the key mediator in cisplatin-induced nephrotoxicity. Mechanistically, excessive expression of Nox4 induced programmed cell death, especially RIP-mediated necroptosis. Finally, we tested whether Nox4 is a potential therapeutic target using an AKI mouse model by injecting a lentivirus-packaged Nox4 shRNA plasmid through tail vein. Disruption of Nox4 led to renal function recovery, kidney damage relief and reduced inflammation. We conclude that Nox4 aggravates cisplatin-induced nephrotoxicity by promoting ROS-mediated programmed cell death and inflammation. Thus Nox4 may serve as a potential therapeutic target in the treatment of AKI.

• Authors: Xiao-Ming Meng, Gui-Ling Ren, Li Gao, Qin Yang, Hai-Di Li, Wei-Feng Wu, 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. 63-78 (01 2018) ISSN: 1530-0307 [Electronic] United States
• PMID: 29106395 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Free Radical Scavengers
• Reactive Oxygen Species
• Recombinant Proteins
• NADPH Oxidase 4
• NOX4 protein, human
• Nox4 protein, mouse
• Cisplatin

Topics

• Acute Kidney Injury (chemically induced, metabolism, pathology, prevention & control)
• Animals
• Antineoplastic Agents (adverse effects, chemistry, pharmacology)
• Apoptosis (drug effects)
• Cell Line, Transformed
• Cells, Cultured
• Cisplatin (adverse effects, antagonists & inhibitors, pharmacology)
• Disease Models, Animal
• Free Radical Scavengers (pharmacology, therapeutic use)
• Gene Expression Regulation (drug effects)
• Humans
• Kidney (drug effects, immunology, metabolism, pathology)
• Kidney Tubules (drug effects, immunology, metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• NADPH Oxidase 4 (antagonists & inhibitors, genetics, metabolism)
• Oxidative Stress (drug effects)
• RNA Interference
• Reactive Oxygen Species (agonists, metabolism)
• Recombinant Proteins (chemistry, metabolism)