Increased plasma phenylacetic acid in patients with end-stage renal failure inhibits iNOS expression
J. Jankowski, … , W. Zidek, M. Tepel
J. Jankowski, … , W. Zidek, M. Tepel
Published July 15, 2003
Citation Information: J Clin Invest. 2003;112(2):256-264. https://doi.org/10.1172/JCI15524.
View: Text | PDF
Article Endocrinology

Increased plasma phenylacetic acid in patients with end-stage renal failure inhibits iNOS expression

Abstract

NO prevents atherogenesis and inflammation in vessel walls by inhibition of cell proliferation and cytokine-induced endothelial expression of adhesion molecules and proinflammatory cytokines. Reduced NO production due to inhibition of either eNOS or iNOS may therefore reinforce atherosclerosis. Patients with end-stage renal failure show markedly increased mortality due to atherosclerosis. In the present study we tested the hypothesis that uremic toxins are responsible for reduced iNOS expression. LPS-induced iNOS expression in mononuclear leukocytes was studied using real-time PCR. The iNOS expression was blocked by addition of plasma from patients with end-stage renal failure, whereas plasma from healthy controls had no effect. Hemofiltrate obtained from patients with end-stage renal failure was fractionated by chromatographic methods. The chromatographic procedures revealed a homogenous fraction that inhibits iNOS expression. Using gas chromatography/mass spectrometry, this inhibitor was identified as phenylacetic acid. Authentic phenylacetic acid inhibited iNOS expression in a dose-dependent manner. In healthy control subjects, plasma concentrations were below the detection level, whereas patients with end-stage renal failure had a phenylacetic acid concentration of 3.49 ± 0.33 mmol/l (n = 41). It is concluded that accumulation of phenylacetic acid in patients with end-stage renal failure inhibits iNOS expression. That mechanism may contribute to increased atherosclerosis and cardiovascular morbidity in patients with end-stage renal failure.

Authors

J. Jankowski, M. van der Giet, V. Jankowski, S. Schmidt, M. Hemeier, B. Mahn, G. Giebing, M. Tölle, H. Luftmann, H. Schlüter, W. Zidek, M. Tepel

×

Figure 4

Options: View larger image (or click on image) Download as PowerPoint
Nitrite formation in ECV304 cells. Nitrite accumulation was measured aft...
Nitrite formation in ECV304 cells. Nitrite accumulation was measured after 30 minutes with (stim) or without (unstim) stimulation of ECV304 with acetylcholine (1 μmol/l). ECV304 cells were stimulated with acetylcholine in the absence (stim) or presence of PAA (0.1 mmol/l, 0.5 mmol/l, 1.0 mmol/l, and 5.0 mmol/l) and L-NAME (10 μmol/l). Data are mean ± SEM (n = 6). *P < 0.05 compared with stimulation. L-NAME, NG-nitro-L-arginine methyl ester.