DDAH-2 alleviates contrast medium iopromide-induced acute kidney injury through nitric oxide synthase.

Abstract

BACKGROUND:

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.

METHODS AND RESULTS:

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.

CONCLUSIONS:

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.

• Authors: Heng-Huei Lin, Tzong-Shyuan Lee, Shing-Jong Lin, Yi-Chen Yeh, Tse-Min Lu, Chiao-Po Hsu
• Journal: Clinical science (London, England : 1979) (Clin Sci (Lond)) Vol. 133 Issue 23 Pg. 2361-2378 (12 12 2019) ISSN: 1470-8736 [Electronic] England
• PMID: 31763675 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Chemical References

• Contrast Media
• Iohexol
• N,N-dimethylarginine
• iopromide
• Arginine
• Nitric Oxide Synthase
• Amidohydrolases
• dimethylargininase

Topics

• Acute Kidney Injury (chemically induced, pathology)
• Amidohydrolases (genetics, metabolism)
• Animals
• Arginine (analogs & derivatives, metabolism)
• Cell Line
• Contrast Media (adverse effects)
• Female
• Humans
• Iohexol (adverse effects, analogs & derivatives)
• Kidney (metabolism, physiopathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Nitric Oxide Synthase (antagonists & inhibitors, metabolism)
• Rats
• Reperfusion Injury (pathology)