Division of Cardiovascular Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.
Department of Physiology, National Yang-Ming University, Taipei, Taiwan.
Clin Sci (Lond). 2019 Dec 12;133(23):2361-2378. doi: 10.1042/CS20190455.
Contrast medium-induced acute kidney injury (CI-AKI) is one of the most common causes of hospital-acquired acute renal failure. However, the pathogenesis of CI-AKI remains unclear. Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide synthase (NOS) inhibitor that is largely metabolised by dimethylarginine dimethylaminohydroxylase (DDAH) in humans. Two isoforms of DDAH exist, namely, DDAH-1 and DDAH-2. In the present study, we examined whether the DDAH-2/ADMA/NOS pathway is involved in the pathogenesis of CI-AKI.
Exposure to the contrast medium iopromide led to increase in creatinine and blood urea nitrogen (BUN) levels, accumulation of ADMA, increase in reactive oxygen species (ROS) generation, and an inflammatory response in mice kidney tissue. The injection of adenovirus-harbouring DDAH-2 lowered renal ADMA levels and had a reno-protective effect against contrast-medium injury by decreasing cell apoptosis, ROS, and fibrosis. By contrast, contrast medium-induced renal injury was exacerbated in heterozygous DDAH-2 knockout mice. In the in vitro study, overexpression of DDAH-2 increased the levels of nitrite and intracellular cGMP, while the DDAH-2 knockdown induced the opposite effect. These findings were also observed in the in vivo sample.
Our findings provide the first evidence that the DDAH-2/ADMA/NOS pathway is involved in the pathogenesis of CI-AKI and that the protective effect of DDAH-2 probably arises from the modulation of NOS activity, oxidative stress, and the inflammatory process.
对比剂诱导的急性肾损伤（CI-AKI）是医院获得性急性肾衰竭的最常见原因之一。然而，CI-AKI 的发病机制仍不清楚。不对称二甲基精氨酸（ADMA）是一种内源性一氧化氮合酶（NOS）抑制剂，在人体内主要由二甲基精氨酸二甲氨基水解酶（DDAH）代谢。DDAH 存在两种同工酶，即 DDAH-1 和 DDAH-2。在本研究中，我们研究了 DDAH-2/ADMA/NOS 途径是否参与 CI-AKI 的发病机制。
暴露于造影剂碘普罗胺会导致小鼠肾脏组织中肌酐和血尿素氮（BUN）水平升高、ADMA 积累、活性氧（ROS）生成增加和炎症反应。注射携带 DDAH-2 的腺病毒可降低肾脏 ADMA 水平，并通过减少细胞凋亡、ROS 和纤维化对造影剂损伤起到肾保护作用。相比之下，杂合型 DDAH-2 敲除小鼠的造影剂诱导的肾损伤加重。在体外研究中，DDAH-2 的过表达增加了亚硝酸盐和细胞内 cGMP 的水平，而 DDAH-2 的敲低则产生了相反的效果。在体内样本中也观察到了这些发现。
我们的研究结果首次提供了证据表明，DDAH-2/ADMA/NOS 途径参与了 CI-AKI 的发病机制，而 DDAH-2 的保护作用可能源于 NOS 活性、氧化应激和炎症过程的调节。
