Increased plasma phenylacetic acid in patients with end-stage renal failure inhibits iNOS expression
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Increased plasma phenylacetic acid in patients with end-stage renal failure inhibits iNOS expression. / Jankowski, J; van der Giet, M; Jankowski, V; Schmidt, S; Hemeier, M; Mahn, B; Giebing, G; Tolle, M; Luftmann, H; Schluter, H; Zidek, W; Tepel, M.
in: J CLIN INVEST, Jahrgang 112, Nr. 2, 07.2003, S. 256-64.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Increased plasma phenylacetic acid in patients with end-stage renal failure inhibits iNOS expression
AU - Jankowski, J
AU - van der Giet, M
AU - Jankowski, V
AU - Schmidt, S
AU - Hemeier, M
AU - Mahn, B
AU - Giebing, G
AU - Tolle, M
AU - Luftmann, H
AU - Schluter, H
AU - Zidek, W
AU - Tepel, M
PY - 2003/7
Y1 - 2003/7
N2 - 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.
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.
KW - Adult
KW - Aged
KW - Animals
KW - Blotting, Western
KW - Cell Line
KW - Cell Survival
KW - Cells, Cultured
KW - Dose-Response Relationship, Drug
KW - Electrophoresis, Polyacrylamide Gel
KW - Female
KW - Gas Chromatography-Mass Spectrometry
KW - Humans
KW - Kidney Failure, Chronic
KW - Leukocytes, Mononuclear
KW - Macrophages
KW - Magnetic Resonance Spectroscopy
KW - Male
KW - Mass Spectrometry
KW - Mice
KW - Middle Aged
KW - Nitric Oxide
KW - Nitric Oxide Synthase
KW - Nitric Oxide Synthase Type II
KW - Nitrites
KW - Phenylacetates
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Journal Article
U2 - 10.1172/JCI15524
DO - 10.1172/JCI15524
M3 - SCORING: Journal article
C2 - 12865413
VL - 112
SP - 256
EP - 264
JO - J CLIN INVEST
JF - J CLIN INVEST
SN - 0021-9738
IS - 2
ER -