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

• Published in: Laboratory investigation Vol. 98; no. 1; pp. 63 - 78
• Main Authors: Meng, Xiao-Ming, Ren, Gui-Ling, Gao, Li, Yang, Qin, Li, Hai-Di, Wu, Wei-Feng, 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; 13/109; 13/2; 13/31; 13/44; 13/51; 14/1; 38/77; 45; 45/41; 45/44; 631/443/272/1684; 64/60; 692/699/1585/4; Acetylcysteine; Acute Kidney Injury - chemically induced; Acute Kidney Injury - metabolism; Acute Kidney Injury - pathology; Acute Kidney Injury - prevention & control; Animals; Antineoplastic Agents - adverse effects; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Biocompatibility; Cell death; Cell injury; Cell Line, Transformed; Cells, Cultured; Chemotherapy; Cisplatin; Cisplatin - adverse effects; Cisplatin - antagonists & inhibitors; Cisplatin - pharmacology; Diabetes mellitus; Diabetic nephropathy; Disease Models, Animal; Free Radical Scavengers - pharmacology; Free Radical Scavengers - therapeutic use; Gene Expression Regulation - drug effects; Humans; Inflammation; Inflammatory response; Injuries; Isoforms; Kidney - drug effects; Kidney - immunology; Kidney - metabolism; Kidney - pathology; Kidney cancer; Kidney diseases; Kidney Tubules - drug effects; Kidney Tubules - immunology; Kidney Tubules - metabolism; Kidney Tubules - pathology; Kidneys; Laboratory Medicine; Male; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; Mortality; mRNA; NAD(P)H oxidase; NADPH Oxidase 4 - antagonists & inhibitors; NADPH Oxidase 4 - genetics; NADPH Oxidase 4 - metabolism; Necroptosis; Nephropathy; NOX4 protein; Oxidase; Oxidative Stress - drug effects; Pathology; Reactive oxygen species; Reactive Oxygen Species - agonists; Reactive Oxygen Species - metabolism; Recombinant Proteins - chemistry; Recombinant Proteins - metabolism; Renal cell carcinoma; Renal function; research-article; RNA Interference; Rodents
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1038/labinvest.2017.120

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.