Contrast-induced acute kidney injury (CIAKI) is a leading cause of acute kidney injury following radiographic procedures. Intrarenal oxidative stress plays a critical role in CIAKI. Nicotinamide adenine dinucleotide 3-phosphate (NADPH) oxidases (Noxs) are important sources of reactive oxygen species (ROS). Among the various types of Noxs, Nox4 is expressed predominantly in the kidney in rodents. Here, we evaluated the role of Nox4 and benefit of Nox4 inhibition on CIAKI using in vivo and in vitro models. HK-2 cells were treated with iohexol, with or without Nox4 knockdown, or the most specific Nox1/4 inhibitor (GKT137831). Effects of Nox4 inhibition on CIAKI mice were examined. Expression of Nox4 in HK-2 cells was significantly increased following iohexol exposure. Silencing of Nox4 rescued the production of ROS, downregulated pro-inflammatory markers (particularly phospho-p38) implicated in CIAKI, and reduced Bax and caspase 3/7 activity, which resulted in increased cellular survival in iohexol-treated HK-2 cells. Pretreatment with GKT137831 replicated these effects by decreasing levels of phospho-p38. In a CIAKI mouse model, even though the improvement of plasma blood urea nitrogen was unclear, pretreatment with GKT137831 resulted in preserved structure, reduced expression of 8-hydroxy-2’-deoxyguanosine (8OHdG) and kidney injury molecule-1 (KIM-1), and reduced number of TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling)-positive cells. These results suggest Nox4 as a key source of reactive oxygen species responsible for CIAKI and provide a novel potential option for prevention of CIAKI.

造影剂引起的急性肾损伤（CIAKI）是放射线照相术后引起急性肾损伤的主要原因。肾内氧化应激在CIAKI中起关键作用。烟酰胺腺嘌呤二核苷酸3-磷酸（NADPH）氧化酶（Noxs）是活性氧（ROS）的重要来源。在各种类型的Nox中，Nox4主要在啮齿动物的肾脏中表达。在这里，我们评估了Nox4的作用以及Nox4抑制作用在体内和体外对CIAKI的作用。楷模。HK-2细胞用碘海醇，有无Nox4抑制或最特异的Nox1 / 4抑制剂（GKT137831）处理。检查了Nox4抑制对CIAKI小鼠的影响。碘海醇暴露后，HK-2细胞中Nox4的表达显着增加。Nox4的沉默挽救了ROS的产生，下调了与CIAKI相关的促炎性标志物（尤其是磷酸化p38），并降低了Bax和caspase 3/7活性，从而导致碘海醇治疗的HK-2细胞的细胞存活率提高。用GKT137831进行的预处理通过降低磷酸化p38的水平来复制这些作用。在CIAKI小鼠模型中，即使血浆血尿素氮的改善尚不清楚，使用GKT137831预处理仍能保留结构，减少8-羟基-2'-脱氧鸟苷（8OHdG）和肾损伤分子1（KIM-1）的表达，并减少TUNEL（末端脱氧核苷酸转移酶dUTP缺口末端标记）阳性细胞的数量。这些结果表明，Nox4是负责CIAKI的活性氧的关键来源，并为预防CIAKI提供了新的潜在选择。