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

Jankowski, Joachim; Giet, M. van der; Jankowski, Vera; Schmidt, Sven; Hemeier, M.; Mahn, B.; Giebing, G.; Tölle, Markus; Luftmann, Heinrich; Schlüter, Hartmut; Zidek, Walter; Tepel, Martín

doi:10.1172/jci200315524

Cited by 100 publications

(37 citation statements)

References 45 publications

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“…The significant increase in LOX-1 expression in the above in vitro studies suggests that elevated plasma levels of this natural eNOS inhibitor, ADMA, found in patients with chronic renal failure and in hypercholesterolemia, may play a pathophysiological role in the development of endothelial dysfunction and early atherosclerosis. Interestingly, it has recently been found that the phenylacetic acid (PAA), a degradation product of phenylalanine, another potent inhibitor of NOS, also accumulates in patients with end-stage renal disease (19). In healthy subjects, PAA was not detectable in plasma, whereas in patients with end-stage renal failure, plasma concentrations of PAA were 3.49 Ϯ 0.33 mmol/l (19).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, it has recently been found that the phenylacetic acid (PAA), a degradation product of phenylalanine, another potent inhibitor of NOS, also accumulates in patients with end-stage renal disease (19). In healthy subjects, PAA was not detectable in plasma, whereas in patients with end-stage renal failure, plasma concentrations of PAA were 3.49 Ϯ 0.33 mmol/l (19). According to Sydow et al (46), ADMA inhibits the conversion of L-(guanidino-15 N 2 )arginine to 15 N-nitrite (a specific index of NOS activity) at concentrations of Ն5 M in human endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

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Upregulation of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in endothelial cells by nitric oxide deficiency

Smirnova¹,

Sawamura²,

Goligorsky³

2004

American Journal of Physiology-Renal Physiology

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Smirnova, I. V., T. Sawamura, and M. S. Goligorsky. Upregulation of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in endothelial cells by nitric oxide deficiency. Am J Physiol Renal Physiol 287: F25-F32, 2004. First published March 9, 2004 10.1152/ajprenal.00449.2003.-Endothelial cell dysfunction (ECD) is emerging as a common denominator for diverse cardiovascular abnormalities associated with inhibition of endothelial nitric oxide (NO) synthase (eNOS). Elevated levels of asymmetric dimethylarginine (ADMA), a potent eNOS inhibitor, are common in renal failure and may contribute to ECD. Through DNA microarray screening of genes modulated in human umbilical vein endothelial cells (HUVEC) by N G -nitro-L-arginine methyl ester (L-NAME), we found a 1.8-fold increase in low-density lipoprotein receptor-1 (LOX-1) expression. LOX-1 is a major endothelial receptor for oxidized low-density lipoproteins (OxLDL) and is assumed to play a role in the initiation and progression of atherosclerosis. Here, we confirmed the upregulation of LOX-1 mRNA and protein level by quantitative RT-PCR and Western blot analysis. Increased expression of LOX-1 was associated with the accumulation of DiI-labeled OxLDL (DiI-OxLDL) in ADMA-and L-NAME-pretreated HUVEC. To evaluate the contribution of LOX-1 in ADMA-induced accumulation of OxLDL by HUVEC, we used the competitive receptor inhibitor, soluble LOX-1. Treatment of HUVEC with soluble LOX-1 was associated with an approximately two-to threefold inhibition of DiI-OxLDL uptake in L-NAME-or ADMA-treated HUVEC. In conclusion, ADMA-or L-NAME-induced NO deficiency leads to the increased expression of LOX-1 mRNA and protein in HUVEC, which in turn results in the accumulation of OxLDL. Competition with LOX-1-soluble extracellular domain reduces OxLDL accumulation. In summary, elevated ADMA levels, i.e., in patients with renal failure, may be responsible for endothelial accumulation of OxLDL via upregulated LOX-1 receptor, thus contributing to endothelial lipidosis and dysfunction. asymmetric dimethylarginine; endothelial dysfunction; chronic renal failure ENDOTHELIAL DYSFUNCTION IS emerging as a common denominator for diverse cardiovascular abnormalities, such as atherosclerosis, diabetes, hypertension, and renal failure. Inhibition of endothelial nitric oxide (NO) synthase (eNOS) is one of the hallmarks of developing endothelial cell dysfunction (2, 9, 15, 37). Impaired endothelium-dependent vasorelaxation precedes the development of clinical manifestations of the disease and is detectable even before angiographic manifestations become apparent (2,9,14,20,36). One of the mechanisms leading to endothelial dysfunction is the accumulation of an endogenous inhibitor of eNOS, asymmetric dimethylarginine (ADMA) (1,8,13,31,43,46). Plasma levels of ADMA are elevated in patients with chronic renal failure (11,21,22,32,34,44,49), hypercholesterolemia (8, 9, 29, 47), occlusive vascular disease, and hypertension (1, 5, 14, 16 -18, 20, 42, 43, 48) and associated with reduced NO production an...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Upregulation of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in endothelial cells by nitric oxide deficiency

Smirnova¹,

Sawamura²,

Goligorsky³

2004

American Journal of Physiology-Renal Physiology

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“…Molar concentrations ranged from a few picomoles per liter for ILs to micromoles per liter for phenylacetic acid. 22,31 The highest mass concentration was detected for the acute phase macromolecule a1-acid glycoprotein. 54 Most frequently reported concentrations concerned b2-microglobulin, indoxyl sulfate, homocysteine, uric acid, and parathyroid hormone (PTH).…”

Section: Overview Of Uremic Toxin Researchmentioning

confidence: 99%

Normal and Pathologic Concentrations of Uremic Toxins

Duranton¹,

Cohen

Smet

et al. 2012

Journal of the American Society of Nephrology

803

764

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An updated review of the existing knowledge regarding uremic toxins facilitates the design of experimental studies. We performed a literature search and found 621 articles about uremic toxicity published after a 2003 review of this topic. Eighty-seven records provided serum or blood measurements of one or more solutes in patients with CKD. These records described 32 previously known uremic toxins and 56 newly reported solutes. The articles most frequently reported concentrations of b2-microglobulin, indoxyl sulfate, homocysteine, uric acid, and parathyroid hormone. We found most solutes (59%) in only one report. Compared with previous results, more recent articles reported higher uremic concentrations of many solutes, including carboxymethyllysine, cystatin C, and parathyroid hormone. However, five solutes had uremic concentrations less than 10% of the originally reported values. Furthermore, the uremic concentrations of four solutes did not exceed their respective normal concentrations, although they had been previously described as uremic retention solutes. In summary, this review extends the classification of uremic retention solutes and their normal and uremic concentrations, and it should aid the design of experiments to study the biologic effects of these solutes in CKD. The uremic syndrome is characterized by the retention of various solutes that would normally be excreted by the kidneys. The substances that interact negatively with biologic functions are called uremic toxins. In the past years, research on uremic toxicity has been very dynamic and resulted in the identification of dozens of retention solutes, including several uremic toxins. In 2003, the European Uremic Toxin Work Group (http://www.uremic-toxins.org/) proposed a classification of 90 retention solutes providing data on normal and pathologic serum concentrations. 1 In 2007, results were further discussed and expanded with the addition of 14 solutes. 2,3 This collaborative work focused on the highest mean or median concentration of the solutes measured in a uremic population and the highest individual uremic concentration. These data were particularly relevant for researchers on uremic toxicity, and they became a successful tool for allowing use of standardized and biologically relevant concentrations in experimental settings. More recently, scientific and technological progress resulted in the identification of many new uremic retention solutes, particularly thanks to nontargeted approaches such as metabolomic and proteomic profiling. 4,5 To maintain experimental guidelines in keeping with current knowledge, it seemed necessary to propose an update of the encyclopedic review.

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“…Phenylacetic acid, also a protein-bound retention solute, inhibits iNOS expression in a dosage-dependent manner. 25 Inhibition of either endogenous NOS or iNOS may reinforce vascular damage. Furthermore, phenylacetic acid inhibits Ca 2ϩ -ATPase activity, increasing intracellular Ca 2ϩ concentrations.…”

Section: Leukocytesmentioning

confidence: 99%