In vivo renal arginine release is impaired throughout development of chronic kidney disease

Chen, Gin‐Fu; Baylis, Chris

doi:10.1152/ajprenal.00487.2009

Cited by 34 publications

(36 citation statements)

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“…In addition, the relative presence of arginine compared with citrulline (Arg/Cit) was progressively lower in more advanced CKD stages, suggesting a lower activity of argininosuccinate synthase (Enzyme Commission [EC] number 6.3.4.5) and/or argininosuccinate lyase (EC4.3.2.1). In an animal model, CKD induced a reduction in the renal uptake of citrulline in the abundance of these enzymes (14). We also found that reduced kidney function was associated with a greater urinary citrulline excretion, confirming that increased citrullinemia was not related to retention but rather, had a metabolic origin.…”

Section: Discussionsupporting

confidence: 68%

Plasma and Urinary Amino Acid Metabolomic Profiling in Patients with Different Levels of Kidney Function

Duranton¹,

Lundin²,

Gayrard³

et al. 2014

Clinical Journal of the American Society of Nephrology

169

124

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SummaryBackground and objectives Patients with CKD display altered plasma amino acid profiles. This study estimated the association between the estimated GFR and urinary and plasma amino acid profiles in CKD patients.Design, setting, participants, & measurements Urine and plasma samples were taken from 52 patients with different stages of CKD, and plasma samples only were taken from 25 patients on maintenance hemodialysis. Metabolic profiling was performed by liquid chromatography coupled with tandem mass spectrometry after phenylisothiocyanate derivatization.Results Most plasma amino acid concentrations were decreased in hemodialysis patients, whereas proline, citrulline, asparagine, asymmetric dimethylarginine, and hydroxykynurenine levels were increased (P,0.05). Both plasma levels and urinary excretion of citrulline were higher in the group of patients with advanced CKD (CKD stages 2 and 3 versus CKD stages 4 and 5; in plasma: 35.9616.3 versus 61.8623.6 mmol/L, P,0.01; in urine: 1.061.2 versus 7.1614.3 mmol/mol creatinine, P,0.001). Plasma asymmetric dimethylarginine levels were higher in advanced CKD (CKD stages 2 and 3, 0.5760.29; CKD stages 4 and 5, 1.0260.48, P,0.001), whereas urinary excretion was lower (2.3760.93 versus 1.5161.43, P,0.001). Multivariate analyses adjusting on estimated GFR, serum albumin, proteinuria, and other covariates revealed associations between diabetes and plasma citrulline (P=0.02) and between serum sodium and plasma asymmetric dimethylarginine (P=0.03). Plasma tyrosine to phenylalanine and valine to glycine ratios were lower in advanced CKD stages (P,0.01).Conclusion CKD patients have altered plasma and urinary amino acid profiles that are not corrected by dialysis. Depending on solutes, elevated plasma levels were associated with increased or decreased urinary excretion, depicting situations of uremic retention (asymmetric dimethylarginine) or systemic overproduction (citrulline). These results give some insight in the CKD-associated modifications of amino acid metabolism, which may help improve their handling.

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Section: Discussionsupporting

confidence: 68%

Plasma and Urinary Amino Acid Metabolomic Profiling in Patients with Different Levels of Kidney Function

Duranton¹,

Lundin²,

Gayrard³

et al. 2014

Clinical Journal of the American Society of Nephrology

169

124

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“…Animals were kept for 8 wk after surgery and were monitored for the development of kidney disease. This time frame is sufficient for animals to develop moderate to severe kidney disease (11), endothelial dysfunction, glomerulosclerosis, and decreased cardiac function (30,33), confirming the development of both CKD and CVD in this model. Renal function was assessed in all groups by measuring urine protein excretion, serum creatinine, and blood urea nitrogen (BUN).…”

Section: Methodssupporting

confidence: 60%

“…This has been referred to as the "L-arginine paradox" and suggests that NO is derived from extracellular sources of L-arginine (34,47). Classified as a semiessential amino acid, the body is normally capable of producing sufficient quantities of L-arginine to sustain homeostasis (40); however, the synthesis of L-arginine occurs primarily in the kidneys and is impaired in CKD (6,11). Supplementation with exogenous L-arginine would therefore be highly beneficial to patients with CKD.…”

Section: Discussionmentioning

confidence: 99%

Voluntary wheel running augments aortic l-arginine transport and endothelial function in rats with chronic kidney disease

Martens

Kuczmarski

Kim

et al. 2014

American Journal of Physiology-Renal Physiology

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. Voluntary wheel running augments aortic L-arginine transport and endothelial function in rats with chronic kidney disease. Am J Physiol Renal Physiol 307: F418 -F426, 2014. First published June 25, 2014 doi:10.1152/ajprenal.00014.2014.-Reduced nitric oxide (NO) synthesis contributes to risk for cardiovascular disease in chronic kidney disease (CKD). Vascular uptake of the NO precursor L-arginine (ARG) is attenuated in rodents with CKD, resulting in reduced substrate availability for NO synthesis and impaired vascular function. We tested the effect of 4 wk of voluntary wheel running (RUN) and/or ARG supplementation on endotheliumdependent relaxation (EDR) in rats with CKD. Twelve-week-old male Sprague-Dawley rats underwent 5 ⁄6 ablation infarction surgery to induce CKD, or SHAM surgery as a control. Beginning 4 wk following surgery, CKD animals either remained sedentary (SED) or received one of the following interventions: supplemental ARG, RUN, or combined RUNϩARG. Animals were euthanized 8 wk after surgery, and EDR was assessed. EDR was significantly impaired in SED vs. SHAM animals after 8 wk, in response to ACh (10 Ϫ9 -10 Ϫ5 M) as indicated by a reduced area under the curve (AUC; 44.56 Ϯ 9.01 vs 100 Ϯ 4.58, P Ͻ 0.05) and reduced maximal response (Emax; 59.9 Ϯ 9.67 vs. 94.31 Ϯ 1.27%, P Ͻ 0.05). AUC was not improved by ARG treatment but was significantly improved above SED animals in both RUN and RUNϩARG-treated animals. Maximal relaxation was elevated above SED in RUNϩARG animals only. L-[ 3 H]arginine uptake was impaired in both SED and ARG animals and was improved in RUN and RUNϩARG animals. The results suggest that voluntary wheel running is an effective therapy to improve vascular function in CKD and may be more beneficial when combined with L-arginine. endothelial dysfunction; chronic kidney disease; L-arginine; exercise ENDOTHELIAL DYSFUNCTION CONTRIBUTES to the development of cardiovascular disease (CVD) in patients with chronic kidney disease (CKD) and is primarily associated with a decrease in nitric oxide (NO) production and impaired endothelium-dependent relaxation (EDR) (32). The decline in endothelial function precedes the development of atherosclerosis (17, 48) and has been extensively studied as a potential therapeutic target to treat CVD; however, the specific mechanisms of endothelial dysfunction in CKD have not been fully elucidated. Patients with CKD are more likely to die of CVD than progress to end-stage renal disease (26, 42); therefore, novel treatments to improve endothelial function in CKD are needed to reduce CVD-related mortality in CKD.Insufficient availability of the NO precursor L-arginine likely contributes to reduced NO synthesis in CKD (6). Interestingly, the use of L-arginine in studies of endothelial dysfunction in late-stage CKD has produced mixed results (7, 16) unlike other conditions where it has been largely effective (8,13,15,24). Evidence from cell culture studies suggests that urea and other uremic toxins inhibit L-arginine uptake into endothelial cells (52, 54) by...

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“…Western blot analysis for ASS and ASL in kidney cortex was described previously [3], as were DDAH isoforms, SOD isoforms and p22phox Western blot techniques [10]. For arginase, rabbit polyclonal arginase II antibody (Santa Cruz, 1:3,000) with goat anti-rabbit IgG-HRP secondary (Bio-Rad, 1:3,000).…”

Section: Methodsmentioning

confidence: 99%

“…There are multiple potential causes of NO deficiency in CKD, including reduction in the NO synthase (NOS) substrate, L -arginine ( L -Arg) [1] since the normal kidney synthesizes most of the circulating L -Arg; this is by enzymatic conversion of citrulline by argininosuccinate synthase (ASS) and lyase (ASL) [2]. We recently reported impaired renal release of L -Arg in renal mass reduction (RMR)-induced CKD [3]. L -Arg is made in proximal tubules and secreted into plasma via transporters including the cationic amino acid transporter (CAT)1 [4].…”

Section: Introductionmentioning

confidence: 99%

Arginine and Asymmetric Dimethylarginine in Puromycin Aminonucleoside-Induced Chronic Kidney Disease in the Rat

et al. 2011

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Background/Aims: Reduced renal L-arginine (L-Arg) synthesis/transport, induction of arginases and increased endogenous NOS inhibitor, asymmetric dimethylarginine (ADMA) will inhibit NO production. This study investigated pathways of L-Arg synthesis/uptake/utilization, ADMA degradation and oxidant/antioxidants in puromycin aminonucleoside (PAN) chronic kidney disease (CKD). Methods: Rats were given low- (LD) or high-dose (HD) PAN and followed for 11 weeks for proteinuria. BP was measured and blood and tissues were harvested and analyzed for abundance of argininosuccinate synthase (ASS) and lyase (ASL), arginase, cationic amino acid transporter (CAT1) and dimethylargininedimethylaminohydrolase (DDAH) in kidney, cortex, aorta and liver. Arginase and DDAH activity, plasma L-Arg and ADMA, renal pathology and creatinine clearances were also measured. Results: PAN caused dose-dependent kidney damage and hypertension and creatinine clearance fell in HD-PAN. Renal ASS fell in HD-PAN, renal cortex and aortic ASL and membrane CAT1 fell in both PAN groups. There was no activation of renal arginase, but aortic arginase increased in LD-PAN. Renal DDAH activity fell moderately in LD-PAN and markedly in HD-PAN where hepatic DDAH activity also fell. Plasma L-Arg was unchanged while ADMA rose moderately and dose-dependently with PAN. There were several indices of oxidative stress which was most prominent in HD-PAN. Conclusion: Reduction in renal ASS/ASL and loss of renal cortex CAT1 compromises renal L-Arg synthesis and release. Loss of aortic CAT1 impairs L-Arg uptake. Increased plasma ADMA was associated with progressive loss of renal DDAH activity. However, loss of renal clearance and falls in hepatic DDAH activity in HD-PAN did not have additive effects on plasma ADMA.

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In vivo renal arginine release is impaired throughout development of chronic kidney disease

Cited by 34 publications

References 36 publications

Plasma and Urinary Amino Acid Metabolomic Profiling in Patients with Different Levels of Kidney Function

Plasma and Urinary Amino Acid Metabolomic Profiling in Patients with Different Levels of Kidney Function

Voluntary wheel running augments aortic l-arginine transport and endothelial function in rats with chronic kidney disease

Arginine and Asymmetric Dimethylarginine in Puromycin Aminonucleoside-Induced Chronic Kidney Disease in the Rat

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