DDAH-2 Alleviates Contrast Medium Iopromide-Induced Acute Kidney Injury Through Nitric Oxide Synthase

Abstract

Background: Contrast-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 metabolized by dimethylarginine dimethylaminohydroxylase (DDAH) in humans. Two isoforms of DDAH exist, namely, DDAH-1 and DDAH-2. In this study, we examined whether the DDAH-2/ADMA/NOS pathway is involved in the pathogenesis of CI-AKI. Methods and Findings: Exposure to the contrast medium iopromide led to increases of creatinine and blood urea nitrogen levels, accumulation of ADMA, increase of 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 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. Interpretation: Our findings provide the first evidence that the DDAH-2/ADMA/NOS pathway might be involved in the pathogenesis of CI-AKI and that the protective effect of DDAH-2 probably is due to the modulation of NOS activity, oxidative stress, and the inflammatory process. Funding Statement: This work was supported by grants from the Ministry of Science and Technology of Taiwan [MOST-103-2314-B-075-046, 106-2314-B-075-044, 107-2314-B-075-060] and Veterans General Hospitals and University System of Taiwan Joint Research Program [VGHUST102-G7-5, 104-G7-5; 105-G7-3]. Declaration of Interests: The authors state: None. Ethics Approval Statement: All animal experiments were performed in accordance with the approved guidelines by the Institutional Animal Care and Use Committee (IACUC) of Taipei Veterans General Hospital (#2016-124).