Metabolomic Profiling of Arginine Metabolome Links Altered Methylation to Chronic Kidney Disease Accelerated Atherosclerosis.

Fri, 2016-06-24 12:00 -- voskuhlt
TitleMetabolomic Profiling of Arginine Metabolome Links Altered Methylation to Chronic Kidney Disease Accelerated Atherosclerosis.
Publication TypeJournal Article
Year of Publication2015
AuthorsMathew AV, Zeng L, Byun J, Pennathur S
JournalJ Proteomics Bioinform
VolumeSuppl 14
Date Published2015 Oct
ISSN0974-276X
Abstract

Atherosclerotic cardiovascular disease is the leading cause of death in patients with chronic kidney disease (CKD), but the mechanisms underlying vascular disease has not been fully understood. As the nitrogen donor in nitric oxide (NO(·)) synthesis, arginine and its metabolic products are integrally linked to vascular health and information. We hypothesized that derangements in this pathway could explain, in part, increased atherosclerotic risk in CKD. We developed a targeted metabolomic platform to profile quantitatively arginine metabolites in plasma by liquid chromatography tandem mass spectrometry (LC/MS). Male low-density lipoprotein receptor defcient (LDLr(-/-)) mice at age 6 weeks were subjected to sham or 5/6 nephrectomy surgery to induce CKD. Subsequently, the animals were maintained on high fat diet for 24 weeks. Targeted metabolomic analysis of arginine metabolites in plasma was performed by isotope dilution LC/MS including asymmetric dimethyl arginine (ADMA), symmetric dimethyl arginine (SDMA), N-mono-methylarginine (NMMA), arginine and citrulline. Although elevated plasma levels of ADMA and SDMA were found in the CKD mice, only higher ADMA level correlated with degree of atherosclerosis. No significant differences were noted in levels of NMMA between the groups. CKD mice had high levels of citrulline and arginine, but ADMA levels had no correlation with either of these metabolites. These fndings strongly implicate altered arginine methylation and accumulation of ADMA, may in part contribute to CKD accelerated atherosclerosis. It raises the possibility that interrupting pathways that generate ADMA or enhance its metabolism may have therapeutic potential in mitigating atherosclerosis.

DOI10.4172/jpb.S14-001
Alternate JournalJ Proteomics Bioinform
PubMed ID26778898
PubMed Central IDPMC4712927
Grant ListDP3 DK094292 / DK / NIDDK NIH HHS / United States
P30 DK089503 / DK / NIDDK NIH HHS / United States
R24 DK082841 / DK / NIDDK NIH HHS / United States
U24 DK097153 / DK / NIDDK NIH HHS / United States