Journal
KIDNEY INTERNATIONAL
Volume 81, Issue 8, Pages 762-768Publisher
ELSEVIER SCIENCE INC
DOI: 10.1038/ki.2011.476
Keywords
asymmetric dimethylarginine; chronic kidney disease; endothelial dysfunction; nitric oxide synthase; signal transduction
Categories
Funding
- Science Frontier Research Promotion Centers (Cardiovascular Research Institute)
- Ministry of Education, Science, Sports, and Culture, Japan
- Kimura Memorial Heart Foundation
- Kidney Foundation
- Grants-in-Aid for Scientific Research [24390334, 22590565, 24659640, 22791042] Funding Source: KAKEN
Ask authors/readers for more resources
Patients with chronic kidney disease have elevated circulating asymmetric dimethylarginine (ADMA). Recent studies have suggested that ADMA impairs endothelial nitric oxide synthase (eNOS) by effects other than competition with the substrate L-arginine. Here, we sought to identify the molecular mechanism by which increased ADMA causes endothelial dysfunction in a chronic kidney disease model. In wild-type mice with remnant kidney disease, blood urea nitrogen, serum creatinine, and ADMA were increased by 2.5-, 2-, and 1.2-fold, respectively, without any change in blood pressure. Nephrectomy reduced endothelium-dependent relaxation and eNOS phosphorylation at Ser1177 in isolated aortic rings. In transgenic mice overexpressing dimethylarginine dimethylaminohydrolase-1, the enzyme that metabolizes ADMA, circulating ADMA was not increased by nephrectomy and was decreased to half that of wild-type mice. These mice did not exhibit the nephrectomy-induced inhibition of both endothelium-dependent relaxation and eNOS phosphorylation. In cultured human endothelial cells, agonist-induced eNOS phosphorylation and nitric oxide production were decreased by ADMA at concentrations less than that of L-arginine in the media. Thus, elevated circulating ADMA may be a cause, not an epiphenomenon, of endothelial dysfunction in chronic kidney disease. This effect may be attributable to inhibition of eNOS phosphorylation. Kidney International (2012) 81, 762-768; doi:10.1038/ki.2011.476; published online 1 February 2012
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available