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.
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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

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Plasma from patients with end-stage renal failure and healthy control su...
Plasma from patients with end-stage renal failure and healthy control subjects show effects of PAA and some of its derivatives on iNOS mRNA expression measured by real-time PCR without (basal; set to 100%) and after stimulation by LPS (1 μg/ml) and IFN-γ (100 U/ml) (control) in mononuclear leukocytes. (a) Expression of iNOS in the presence of various amounts of plasma diluted in PBS from patients with CRF on regular hemodialysis (end-stage renal failure) in the presence of plasmas from healthy persons (healthy). The plasma was diluted with physiologic salt solution 1/10, 1/2, and 1/1, respectively. Basal unstimulated iNOS expression was set to 100%; each n = 6. (b) Expression iNOS in the presence of various concentrations of PAA (0.05 mmol/l, 0.1 mmol/l, 0.5 mmol/l, 1.0 mmol/l, and 2.0 mmol/l). Control value as in a. Basal unstimulated iNOS expression was set to 100%. (c) Expression of iNOS in the presence of homogentisic acid (HGA; 1.0 mmol/l), phenylethyl amine (PEA; 1.0 mmol/l), or phenylalanine (PhA; 1.0 mmol/l) (n = 6). *P < 0.05 compared with control.