Arginine, citrulline, and nitric oxide metabolism in end-stage renal disease patients

Lau, Titus; Owen, William F.; Yu, Yong Ming; Noviski, Natan; Lyons, Jeremy; Zurakowski, David; Tsay, Rita; Ajami, Alfred M.; Young, Vernon R.; Castillo, Leticia

doi:10.1172/jci7199

Cited by 116 publications

(101 citation statements)

References 32 publications

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“…Indeed, renal L-arginine synthesis is significantly reduced (to approximately 40% of normal levels) in CKD patients; 24 however, plasma levels of L-arginine in patients with renal disease are at the low end of the normal range and are always well in excess of the K m of NOS enzymes. [2][3][4] Further, net endogenous L-arginine synthesis is preserved in ESRD patients, 7 presumably because of compensatory increases in production by nonrenal tissues.…”

Section: Regulation Of Substrate Availabilitymentioning

confidence: 99%

“…[2][3][4] Similar conclusions have been reached by Blum et al 5 and Wever and colleagues 6 (the latter group measured conversion of 15 N 2 -labeled arginine to citrulline in people with CKD). Although Lau and co-workers reported increased rates of arginine conversion to citrulline in ESRD patients 7 -perhaps reflecting activation of inducible nitric oxide synthase [NOS] by hemodialysis-most evidence indicates that total NO production is decreased in humans with CKD or ESRD compared with healthy individuals. In the absence of acute inflammatory events, decreased total NO production (expressed as the qualitative index UNO X V [urinary excretion of NO X ]) has also been reported in animal models of CKD.…”

Section: Introductionmentioning

confidence: 99%

“…[14][15][16][17][18] Although no clinical evidence is available, animal studies implicate intrarenal NO deficiency in CKD, and this is another factor that would contribute to falls in the UNO X V index. [7][8][9][10][11][12][13] Given the persistent oxidative stress induced in early-stage CKD, 19 reduced NO synthesis is likely to be widespread in both CKD and ESRD (see below).…”

Section: Introductionmentioning

confidence: 99%

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Arginine, arginine analogs and nitric oxide production in chronic kidney disease

2006

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SummaryNitric oxide (NO) production is reduced in renal disease, partially due to decreased endothelial NO production. Evidence indicates that NO deficiency contributes to cardiovascular events and progression of kidney damage. Two possible causes of NO deficiency are substrate (L-arginine) limitation and increased levels of circulating endogenous inhibitors of NO synthase (particularly asymmetric dimethylarginine [ADMA]). Decreased L-arginine availability in chronic kidney disease (CKD) is due to perturbed renal biosynthesis of this amino acid. In addition, inhibition of transport of L-arginine into endothelial cells and shunting of L-arginine into other metabolic pathways (e.g. those involving arginase) might also decrease availability. Elevated plasma and tissue levels of ADMA in CKD are functions of both reduced renal excretion and reduced catabolism by dimethylarginine dimethylaminohydrolase (DDAH). The latter might be associated with loss-offunction polymorphisms of a DDAH gene, functional inhibition of the enzyme by oxidative stress in CKD and end-stage renal disease, or both. These findings provide the rationale for novel therapies, including supplementation of dietary L-arginine or its precursor L-citrulline, inhibition of non-NOproducing pathways of L-arginine utilization, or both. Because an increase in ADMA has emerged as a major independent risk factor in end-stage renal disease (and probably also in CKD), lowering ADMA concentration is a major therapeutic goal; interventions that enhance the activity of the ADMA-hydrolyzing enzyme DDAH are under investigation.

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Section: Regulation Of Substrate Availabilitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Arginine, arginine analogs and nitric oxide production in chronic kidney disease

2006

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“…15 Moreover, L-citrulline can become the effective precursor of L-arginine which is a substrate for endothelial NO synthase (eNOS) via the L-citrulline/L-arginine pathway, and plays an important role in the metabolism and regulation of NO. 16 Others demonstrated that oral supplementation of L-citrulline can inhibition the increased inducible nitric oxide synthase (iNOS) activity, upregulate endothelial NO synthase (eNOS) activity, and improve endothelial function in animal. [17][18][19] The purpose of this present study was to evaluate the protective effects of L-citrulline supplementation on the glycerol-induced ARF in rats, and its underlying mechanism.…”

Section: Introductionmentioning

confidence: 99%

L-Citrulline Protects Against Glycerol-Induced Acute Renal Failure in Rats

Liu

Gou

et al. 2013

Renal Failure

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There is an increasing evidence that oxidative stress plays an important role in the pathogenesis of rhabdomyolysisinduced acute renal failure (ARF). In this study, protective effects of L-citrulline on glycerol-induced ARF in rats were investigated. Six groups of rats were employed in this study: group 1 served as a control; group 2 was only given glycerol (50%, 10 mL/kg, i.m.); group 3 was given glycerol plus dexamethasone (0.1 mg/kg, i.g.) as positive reference drug, starting at the same time as the glycerol injections; the last three groups were given glycerol plus L-citrulline (300, 600, and 900 mg/kg, i.g.) respectively, starting at the same time as the glycerol injections. The injections of glycerol were only once, and after glycerol injections the i.g. administrations of dexamethasone and L-citrulline were repeated every 24 h for 7 days. After 7 days of glycerol injections, the blood samples and kidney tissues were harvested for future biochemical and pathology analyses. The levels of creatinine (Cr) and urea nitrogen (BUN) in plasma, the content of malondialdehyde (MDA), glutathione (GSH), nitric oxide (NO), the activity of total nitric oxide synthase (TNOS), inducible nitric oxide synthase (iNOS), endothelial NO synthase (eNOS), and superoxide dismutase (SOD) were evaluated in kidney tissues. Consequently, administrations of L-citrulline improved an impaired intrarenal oxygenation and kidney function compared with the glycerol group, and prevented the renal oxidative stress damage as well as severe functional and morphological renal deterioration. Therefore, L-citrulline might have potential application in the amelioration of glycerol-induced ARF.

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“…There was good agreement between these two approaches for estimating the rates of NO synthesis. We have not yet applied this approach in studies with burn patients, but we have used it in recent studies of NO production in patients with end-stage renal disease (Lau et al 2000). As summarized in Table 3, we found markedly higher rates of NO production in patients with end-stage renal disease, in comparison with rates measured earlier in healthy adults (Castillo et al 1996).…”

Section: Metaprobes Are Dynamic Biomarkersmentioning

confidence: 72%

Metabolism 2000: the emperor needs new clothes

Young

Ajami

2001

Proc. Nutr. Soc.

Self Cite

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Professor Vernon R. Young, fax +1 617 253 9658, email vryoung@mit.edu Metabolism is one of the corner stones of nutritional science. As biology enters the post-genomic era and with functional genomics beginning to take off, we anticipate that the study of metabolism will play an increasingly important role in helping to link advances made via the reductionist paradigm, that has been so successful in molecular and cellular biology, with those emerging from observational studies in animals and human subjects. A reconstructive metabolically-focused approach offers a timely paradigm for enhancing the elegance of nutritional science. Here we give particular attention to the use of tracers as phenotyping tools and discuss the application of our metaprobe concepts with respect to some novel features of metabolism, including 'underground metabolism', 'metabolic hijacking', 'catalytic promiscuity' and 'moonlighting proteins'. The opportunities for enhancing the study of metabolism by new and emerging technologies, and the importance of the interdisciplinary research enterprise are also touched upon. We conclude that: (1) the metaprobe concepts and approach, discussed herein, potentially yield a quantitative physiological (metabolic) phenotype against which to elaborate partial or focused genotypes; (2) physiological (metabolic) phenotypes which have a whole-body or kinetically-discernible inter-organ tissue-directed metabolic signature are an ideal target for this directed tracer-based definition of the 'functional' genotype; (3) metabolism, probed with tracer tool kits suitable for measuring rates of turnover, change and conversion, becomes in the current sociology of the 'Net', like AOL, Yahoo, Alta Vista, Lycos or Ask Jeeves, the portal for an exploration of the metabolic characteristics of the 'Genomics Internet'. Metabolism: Metaprobe: Tracers: Physiological (metabolic) phenotypes GSH, glutathione. ' "But he hasn't got anything on" a little child said.'

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Arginine, citrulline, and nitric oxide metabolism in end-stage renal disease patients

Cited by 116 publications

References 32 publications

Arginine, arginine analogs and nitric oxide production in chronic kidney disease

Arginine, arginine analogs and nitric oxide production in chronic kidney disease

L-Citrulline Protects Against Glycerol-Induced Acute Renal Failure in Rats

Metabolism 2000: the emperor needs new clothes

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