Circulating methylarginine levels and the decline in renal function in patients with chronic kidney disease are modulated by DDAH1 polymorphisms

Caplin, B. et al. (2010) Circulating methylarginine levels and the decline in renal function in patients with chronic kidney disease are modulated by DDAH1 polymorphisms. Kidney International, 77(5), pp. 459-467. (doi: 10.1038/ki.2009.463) (PMID:20010544)

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In patients with chronic kidney disease, high plasma levels of the endogenous nitric oxide synthase inhibitor, asymmetric dimethylarginine, are thought to contribute to decline in renal function. Here we took a candidate gene approach to determine any causal role of asymmetric dimethylarginine in the progression of chronic kidney disease. The impact of single-nucleotide polymorphisms in the genes encoding the two isoforms of the asymmetric dimethylarginine-degrading enzyme, dimethylarginine dimethylaminohydrolase (DDAH1 and DDAH2), on enzyme expression, plasma asymmetric dimethylarginine levels, and longitudinal changes in estimated glomerular filtration rate were determined in various patient groups. There was evidence suggesting that the rs17384213 DDAH1 GG genotype was associated with increased expression of its mRNA in kidney allografts. Healthy subjects carrying the rs17384213 G allele had lower plasma asymmetric dimethylarginine, and a similar borderline association was found in patients with chronic kidney disease. This allele, however, was independently associated with a steeper decline in renal function in two separate cohorts of patients with chronic kidney disease. We conclude that polymorphisms in DDAH1 alter the rate of decline of glomerular filtration rate in subjects with chronic kidney disease. Our findings show that DDAH1 modulates plasma asymmetric dimethylarginine and contributes to the decline in renal function. However, it appears that increases in circulating methylarginine did not mediate progressive kidney injury.

Item Type:Articles
Keywords:Arginine, asymmetric dimethylarginine, cardiovascular risk, expression, fibrosis, gene, human plasma, impact, nitric oxide, nitric-oxide synthesis, plasma, polymorphism, polymorphisms, progression, progression of chronic renal failure
Glasgow Author(s) Enlighten ID:Leiper, Professor James
Authors: Caplin, B., Nitsch, D., Gill, H., Hoefield, R., Blackwell, S., MacKenzie, D., Cooper, J. A., Middleton, R. J., Talmud, P. J., Veitch, P., Norman, J., Wheeler, D. C., and Leiper, J. M.
College/School:College of Science and Engineering > School of Engineering > Electronics and Nanoscale Engineering
Journal Name:Kidney International
Journal Abbr.:Kidney int.
Publisher:Nature Publishing Group
ISSN (Online):1523-1755
Published Online:16 December 2015

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