Increased plasma phenylacetic acid in patients with end-stage renal failure inhibits iNOS expression.
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.
Jankowski
J
J
Medizinische Klinik IV, Universitätsklinikum Benjamin Franklin, Freie Universität, Berlin, Germany. Joachim.Jankowski@medizin.fu-berlin.de
van der Giet
M
M
Jankowski
V
V
Schmidt
S
S
Hemeier
M
M
Mahn
B
B
Giebing
G
G
Tolle
M
M
Luftmann
H
H
Schluter
H
H
Zidek
W
W
Tepel
M
M
D000328:Adult; D000368:Aged; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007676:Kidney Failure, Chronic / Q000097:blood*; D007963:Leukocytes, Mononuclear / Q000201:enzymology / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000378:metabolism; D010648:Phenylacetates / Q000097:blood*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D009573:Nitrites; D010648:Phenylacetates; D009569:Nitric Oxide; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C025136:phenylacetic acid