TY - JOUR AU - Jankowski, J. AU - van der Giet, M. AU - Jankowski, V. AU - Schmidt, S. AU - Hemeier, M. AU - Mahn, B. AU - Giebing, G. AU - Tölle, M. AU - Luftmann, H. AU - Schlüter, H. AU - Zidek, W. AU - Tepel, M. T1 - Increased plasma phenylacetic acid in patients with end-stage renal failure inhibits iNOS expression PY - 2003/07/15/ AB - 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. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI15524 VL - 112 IS - 2 UR - https://doi.org/10.1172/JCI15524 SP - 256 EP - 264 PB - The American Society for Clinical Investigation ER -