Deletion of NADPH oxidase 2 attenuates cisplatin-induced acute kidney injury through reducing ROS-induced proximal tubular cell injury and inflammation

Ho-Ching Chen; Hsin-Yu Hou; Junne-Ming Sung; Chi-Chang Shieh

doi:10.3389/fmed.2023.1097671

Deletion of NADPH oxidase 2 attenuates cisplatin-induced acute kidney injury through reducing ROS-induced proximal tubular cell injury and inflammation

Front Med (Lausanne). 2023 Mar 13:10:1097671. doi: 10.3389/fmed.2023.1097671. eCollection 2023.

Authors

Ho-Ching Chen^{1

2}, Hsin-Yu Hou¹, Junne-Ming Sung^{1

3}, Chi-Chang Shieh^{1

4}

Affiliations

¹ Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
² Renal Division, Department of Internal Medicine, Cishan Hospital, Ministry of Health and Welfare, Kaohsiung, Taiwan.
³ Renal Division, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan.
⁴ Department of Pediatrics, National Cheng Kung University Hospital, Tainan, Taiwan.

Abstract

Backgrounds: Cisplatin is a commonly used chemotherapeutic agent in cancer treatment. However, its high nephrotoxicity limits its therapeutic application and efficacy. Cisplatin induces nephrotoxicity mainly through oxidative stress and inflammation. Reactive oxygen species (ROS) in the kidneys mainly arise from nicotinamide adenine dinucleotide phosphate (NADPH) oxidases 2 (NOX2), which is highly upregulated during ischemia-reperfusion injury and diabetes mellitus. However, its role in cisplatin-induced acute kidney injury (AKI) remains unknown.

Methods: A 8-10-week-old NOX2 gene-knockout and wild-type mice were injected with 25 mg/kg cisplatin intraperitoneally for experiments.

Results: We investigated the role of NOX2 in cisplatin-induced AKI and found that NOX2-mediated ROS production is a key inflammatory mediator of proximal tubular cell injury in cisplatin-induced AKI. NOX2 gene-knockout alleviated cisplatin-induced renal function decline, tubular injury score, kidney injury molecule-1(Kim-1) expression, and interleukin (IL)-6 and IL-1α levels with a reduction of ROS production. Moreover, in cisplatin-induced AKI, intercellular adhesion molecule 1 (ICAM-1) and the chemoattractant CXC ligand 1 (CXCL1) were highly expressed in association with neutrophil infiltration, which were all attenuated by deletion of NOX2.

Conclusion: These data indicate that NOX2 aggravates cisplatin nephrotoxicity by promoting ROS-mediated tissue injury and neutrophil infiltration. Thus, appropriate targeting of NOX2/ROS pathway may minimize the risk of cisplatin-induced kidney injury in patients receiving cancer therapy.

Keywords: ICAM-1 NOX2 modulates cisplatin-induced nephrotoxicity; NOX2; ROS; cisplatin-induced AKI; neutrophil infiltration.