Abstract：
An adverse outcome pathway (AOP) is a conceptual construct of causally and sequentially linked events, which occur during exposure to stressors, with an adverse outcome relevant to risk assessment. The development of an AOP is a means of identifying knowledge gaps in order to prioritize research assessing the health risks associated with exposure to physical or chemical stressors. In this paper, a review of knowledge was proposed, examining experimental and epidemiological data, in order to identify relevant key events and potential key event relationships in an AOP for renal impairment, relevant to stressors such as uranium (U). Other stressors may promote similar pathways, and this review is a necessary step to compare and combine knowledge reported for nephrotoxicants. U metal ions are filtered through the glomerular membrane of the kidneys, then concentrate in the cortical and juxtaglomerular areas, and bind to the brush border membrane of the proximal convoluted tubules. U uptake by epithelial cells occurs through endocytosis and the sodium-dependent phosphate co-transporter (NaPi-IIa). The identified key events start with the inhibition of the mitochondria electron transfer chain and the collapse of mitochondrial membrane potential, due to cytochrome b5/cytochrome c disruption. In the nucleus, U directly interacts with negatively charged DNA phosphate, thereby inducing an adduct formation, and possibly DNA strand breaks or cross-links. U also compromises DNA repair by inhibiting zing finger proteins. Thereafter, U triggers the Nrf2, NF-κB, or endoplasmic reticulum stress pathways. The resulting cellular key events include oxidative stress, DNA strand breaks and chromosomal aberrations, apoptosis, and pro-inflammatory effects. Finally, the main adverse outcome is tubular damage of the S2 and S3 segments of the kidneys, leading to tubular cell death, and then kidney failure. The attribution of renal carcinogenesis due to U is controversial, and specific experimental or epidemiological studies must be conducted. A tentative construction of an AOP for uranium-induced kidney toxicity and failure was proposed.
摘要：
不良结局途径(AOP)是因果关系和顺序关联事件的概念结构，发生在暴露于压力源期间，与风险评估相关的不良结果。AOP的开发是确定知识差距的一种手段，以便优先考虑评估与暴露于物理或化学压力源相关的健康风险的研究。在本文中,提出了知识审查，检查实验和流行病学数据，为了确定肾损害AOP中的相关关键事件和潜在关键事件关系，与铀(U)等压力源相关。其他压力源可能会促进类似的途径，这篇综述是比较和结合肾毒性药物知识的必要步骤。U金属离子通过肾脏的肾小球膜过滤，然后集中在皮质和肾小球附近，并结合到近端回旋小管的刷状缘膜上。上皮细胞的U摄取通过内吞作用和钠依赖性磷酸盐共转运蛋白（NaPi-IIa）发生。确定的关键事件始于线粒体电子转移链的抑制和线粒体膜电位的崩溃，由于细胞色素b5/细胞色素c破坏。在细胞核中，U直接与带负电荷的DNA磷酸相互作用，从而诱导加合物形成，和可能的DNA链断裂或交联。U还通过抑制手指蛋白来损害DNA修复。此后,U触发Nrf2，NF-κB，或内质网应激途径。由此产生的细胞关键事件包括氧化应激，DNA链断裂和染色体畸变,凋亡，和促炎作用。最后,主要的不良结果是肾脏S2和S3节段的肾小管损伤，导致肾小管细胞死亡，然后是肾衰竭.由于U引起的肾癌的归属是有争议的，必须进行特定的实验或流行病学研究。提出了一种用于铀诱导的肾毒性和衰竭的AOP的初步构建。
