Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China.
Department of Nephrology, Kidney Research Institute, West China Hospital, Sichuan University, Chengdu 610041, China.
Theranostics. 2023 May 8;13(9):2863-2878. doi: 10.7150/thno.81240. eCollection 2023.
Sepsis is a severe clinical syndrome featured through organ dysfunction due to infection, while the accompanying acute kidney injury (AKI) is linked to significant incidence of morbidity as well as mortality. Recently, emerging evidence has revealed that nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) is implicated in various renal diseases, while its role and modulation in septic acute kidney injury (S-AKI) remains largely unknown. , S-AKI in wild-type and renal tubular epithelial cell (RTEC)-specific NOX4 knockout mice was induced by lipopolysaccharides (LPS) injection or cecal ligation and puncture (CLP). , TCMK-1 (mouse kidney tubular epithelium cell line) cells were treated with LPS. Serum and supernatant biochemical, mitochondrial dysfunctional, inflammatory and apoptotic parameters were measured and compared across groups. The activation of reactive oxygen species (ROS) and NF-κB signaling was also assessed. NOX4 was predominantly upregulated in RTECs of S-AKI mouse model induced by LPS/CLP and cultured TCMK-1 cells exposed to LPS. RTEC-specific deletion of NOX4 or pharmacological inhibition of NOX4 by GKT137831 both alleviated LPS/CLP-injured renal function and pathology in mice. Furthermore, NOX4 inhibition alleviated mitochondrial dysfunction supported by ultrastructural damage, reduction of ATP production and mitochondrial dynamics imbalance, together with inflammation and apoptosis in kidney injured by LPS/CLP and TCMK-1 cells injured by LPS, while NOX4 overexpression aggravated the above-mentioned indices in TCMK-1 cells with LPS stimulation. Mechanism-wise, the raised NOX4 in RTECs may induce ROS and NF-κB signaling activation in S-AKI. Collectively, genetic or pharmacological inhibition of NOX4 protects from S-AKI by reducing generation of ROS and activation of NF-κB signal, which suppress mitochondrial dysfunction, inflammation together with apoptosis. NOX4 may act as a novel target for the S-AKI therapy.
脓毒症是一种严重的临床综合征，其特征为感染导致的器官功能障碍，而伴随的急性肾损伤（AKI）则与较高的发病率和死亡率密切相关。最近，新出现的证据表明，烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶 4（NOX4）与多种肾脏疾病有关，但其在脓毒症急性肾损伤（S-AKI）中的作用和调节仍知之甚少。在这里，我们研究了 NOX4 在 S-AKI 中的作用和机制。通过脂多糖（LPS）注射或盲肠结扎和穿孔（CLP）诱导野生型和肾小管上皮细胞（RTEC）特异性 NOX4 敲除小鼠的 S-AKI，使用 TCMK-1（小鼠肾管状上皮细胞系）细胞进行 LPS 处理。测量并比较了各组的血清和上清液生化、线粒体功能障碍、炎症和凋亡参数。还评估了活性氧（ROS）和 NF-κB 信号的激活。结果表明，LPS/CLP 诱导的 S-AKI 小鼠模型和 LPS 处理的培养 TCMK-1 细胞中，NOX4 在 RTEC 中主要上调。RTEC 特异性的 NOX4 缺失或通过 GKT137831 抑制 NOX4 均可减轻 LPS/CLP 损伤的肾功能和病理学。此外，NOX4 抑制减轻了 LPS/CLP 损伤肾脏和 LPS 刺激的 TCMK-1 细胞损伤中的线粒体功能障碍，这一作用由超微结构损伤、ATP 产生减少和线粒体动力学失衡来支持，同时还减轻了炎症和凋亡。而 LPS 刺激的 TCMK-1 细胞中过表达 NOX4 则加重了上述指标。从机制上讲，RTEC 中升高的 NOX4 可能会诱导 S-AKI 中 ROS 和 NF-κB 信号的激活。综上所述，NOX4 的遗传或药理学抑制通过减少 ROS 的产生和 NF-κB 信号的激活来保护 S-AKI，从而抑制线粒体功能障碍、炎症和凋亡。NOX4 可能成为 S-AKI 治疗的新靶点。
