The human liver clears both asymmetric and symmetric dimethylarginine

Siroen, Michiel P. C.; Sijp, Joost R.M. van der; Teerlink, Tom; Schaik, Cors van; Nijveldt, Robert J.; Leeuwen, Paul A. M. van

doi:10.1002/hep.20579

Cited by 85 publications

(92 citation statements)

References 36 publications

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“…Liver lysates displayed four-to eightfold higher levels of free cellular ADMA and SDMA compared with the lung and heart. Because liver proteins did not exhibit a higher degree of protein-incorporated methylarginine, the increased ADMA and SDMA levels may be a result of active hepatic methylarginine uptake by the y ϩ transporter, as suggested in previously published studies (31,32). Liver lysates also exhibited significantly higher DDAH1 expression and ADMA degradation activity than did lysates from lung and heart tissue.…”

Section: Discussionmentioning

confidence: 50%

Analysis of methylarginine metabolism in the cardiovascular system identifies the lung as a major source of ADMA

Bulau¹,

Zakrzewicz²,

Kitowska³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

121

103

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, and symmetric dimethylarginine (SDMA), all characterized by methylation of one or both guanidine nitrogen atoms of arginine. L-NMMA and ADMA, but not SDMA, are competitive inhibitors of all nitric oxide synthase isoforms. SDMA is eliminated almost entirely by renal excretion, whereas L-NMMA and ADMA are further metabolized by dimethylarginine dimethylaminohydrolase (DDAH). To explore the interplay between methylarginine synthesis and degradation in vivo, we determined PRMT expression and DDAH activity in mouse lung, heart, liver, and kidney homogenates. In addition, we employed HPLC-based quantification of protein-incorporated and free methylarginine, combined with immunoblotting for the assessment of tissue-specific patterns of arginine methylation. The salient findings of the present investigation can be summarized as follows: 1) pulmonary expression of type I PRMTs was correlated with enhanced protein arginine methylation; 2) pulmonary ADMA degradation was undertaken by DDAH1; 3) bronchoalveolar lavage fluid and serum exhibited almost identical ADMA/SDMA ratios, and 4) kidney and liver provide complementary routes for clearance and metabolic conversion of circulating ADMA. Together, these observations suggest that methylarginine metabolism by the pulmonary system significantly contributes to circulating ADMA and SDMA levels. protein arginine methyltransferases; asymmetric dimethylarginine; dimethylarginine dimethylaminohydrolase

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Section: Discussionmentioning

confidence: 50%

Analysis of methylarginine metabolism in the cardiovascular system identifies the lung as a major source of ADMA

Bulau¹,

Zakrzewicz²,

Kitowska³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

121

103

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“…This calculation corrects a possible overestimation of the fractional renal extraction [calculated as (A Ϫ V)/A ϫ 100% (37,43,53)] in cases of a low renal plasma flow (3). A positive RPCL indicates net clearance of the substance from the blood, whereas a negative RPCL indicates net release into the blood.…”

Section: Methodsmentioning

confidence: 88%

“…This indicates that the plasma clearance of SDMA is not exclusively assigned to the kidney and implies that the plasma concentration of SDMA is not solely regulated by plasma clearance, as the plasma concentration is the result of the balance between production and clearance. Siroen et al (43) showed that the human liver also takes up substantial amounts of SDMA (and ADMA) from the portal and systemic circulation, which shows that the liver also contributes to the plasma clearance of SDMA. However, the results of a study (27) in subjects with hepatorenal syndrome suggested that renal dysfunction is the main determinant of increased SDMA concentration.…”

Section: Discussionmentioning

confidence: 99%

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Reduced renal plasma clearance does not explain increased plasma asymmetric dimethylarginine in hypertensive subjects with mild to moderate renal insufficiency

Ronden

Houben

Teerlink

et al. 2012

American Journal of Physiology-Renal Physiology

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PW, Kroon AA. Reduced renal plasma clearance does not explain increased plasma asymmetric dimethylarginine in hypertensive subjects with mild to moderate renal insufficiency. Am J Physiol Renal Physiol 303: F149 -F156, 2012. First published May 2, 2012 doi:10.1152/ajprenal.00045.2012.-Plasma concentrations of the nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) increase already in the early stages of renal insufficiency. There is no agreement as to whether reduced renal plasma clearance (RPCL) contributes to this increase. Therefore, we investigated the relationship between estimated glomerular filtration rate (eGFR), RPCL, and plasma ADMA and SDMA in essential hypertensive patients with mild to moderate renal insufficiency. In 171 patients who underwent renal angiography, we drew blood samples from the aorta and both renal veins and measured mean renal blood flow (MRBF) using the 133 Xe washout technique. RPCL was calculated using arteriovenous concentration differences and MRBF. After correction for potential confounders, reduced eGFR was associated with higher plasma ADMA and SDMA [standardized regression coefficient (␤) ϭ Ϫ0.22 (95% confidence intervals: Ϫ0.41, Ϫ0.04) and ␤ ϭ Ϫ0.66 (95% confidence intervals: Ϫ0.83, Ϫ0.49), respectively]. However, eGFR was not independently associated with RPCL of ADMA. Moreover, reduced RPCL of ADMA was not associated with higher plasma ADMA. Contrary to ADMA, reduced eGFR was indeed associated with lower RPCL of SDMA [␤ ϭ 0.21 (95% confidence intervals: 0.02, 0.40)]. In conclusion, our findings indicate that RPCL of ADMA is independent of renal function in hypertensive patients with mild to moderate renal insufficiency. Unlike the case for SDMA, reduced RPCL of ADMA is of minor importance for the increase in plasma ADMA in these patients, which indicates that increased plasma ADMA in this population is not a direct consequence of the kidneys failing as a plasma ADMA-regulating organ. dimethylarginines; renal function; hypertension IN PATIENTS with chronic kidney disease (CKD), the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) and its structural isomer symmetric dimethylarginine (SDMA) build up in plasma even in the early stages of renal insufficiency (10,19,21). Moreover, ADMA already rises in incipient CKD. The exact mechanisms responsible for this increase of ADMA and SDMA at these early stages of CKD have not been totally clarified but are likely to involve changes in the regulation of the plasma concentration by the kidneys' renal plasma clearance (RPCL) (37,49).The kidneys play an important role in the plasma concentration regulation of ADMA and SDMA. By measuring arteriovenous concentration differences, a previous study (37) demonstrated that the kidneys clear substantial amounts of ADMA and SDMA from the circulation. Furthermore, both dimethylarginines are excreted in the urine in amounts, which are dependent on the glomerular filtration rate (GFR) (2,30,31,49). However, the main...

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“…Indeed, recent evidence does support a role for hepatic clearance of ADMA by DDAH. 21,22 Thus, with increased cholestatic liver damage there appears to be diminished capacity for hepatic ADMA metabolism contributing to increased circulatory levels, thereby perpetuating increased hepatic vascular tone.…”

mentioning

confidence: 99%

A gas, an amino acid, and an imposter: The story of nitric oxide, l-arginine, and ADMA in portal hypertension

Langer

Shah

2005

Hepatology

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The human liver clears both asymmetric and symmetric dimethylarginine

Cited by 85 publications

References 36 publications

Analysis of methylarginine metabolism in the cardiovascular system identifies the lung as a major source of ADMA

Analysis of methylarginine metabolism in the cardiovascular system identifies the lung as a major source of ADMA

Reduced renal plasma clearance does not explain increased plasma asymmetric dimethylarginine in hypertensive subjects with mild to moderate renal insufficiency

A gas, an amino acid, and an imposter: The story of nitric oxide, l-arginine, and ADMA in portal hypertension

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