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

Chen, Gin‐Fu; Moningka, Natasha C.; Sasser, Jennifer M.; Zharikov, Sergey; Cunningham, Mark; Tain, You‐Lin; Schwartz, Idit F.; Baylis, Chris

doi:10.1159/000334740

Cited by 14 publications

(11 citation statements)

References 43 publications

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“…The conversion of arginine into citrulline, a proxy for NO production, was not affected by partial nephrectomy in this study. Other authors have reported a decrease in the production of NO in chronic kidney disease (2,6). The reason for the discrepancy between our data and previous reports may be due to the higher plasma arginine concentration observed in our animals, or that more time after the renal injury is needed for the development of a full renal dysfunction model to become established.…”

Section: Chronic Nephrectomy Reduces Clearance Of Citrulline and De Ncontrasting

confidence: 96%

“…The terminal half-life () after reaching pseudoequilibrium (min) and mean residence time (MRT; min) were calculated as ϭ Ln(2) ր d (6) and MRT ϭ AUMC ր AUC (7) Because of the different kinetics between the LIG and SHAM groups for the arginine produced from the citrulline bolus dose, no single equation could be fitted. Thus the trapezoidal rule was utilized to obtain the AUC between 0 and 70 min for the 15 N and 15 N4 arginine data.…”

Section: Calculationsmentioning

confidence: 99%

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Extrarenal citrulline disposal in mice with impaired renal function

Marini

Didelija

Fiorotto

2014

American Journal of Physiology-Renal Physiology

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The endogenous synthesis of arginine, a semiessential amino acid, relies on the production of citrulline by the gut and its conversion into arginine by the kidney in what has been called the "intestinal-renal axis" for arginine synthesis. Although the kidney is the main site for citrulline disposal, it only accounts for ~60-70% of the citrulline produced. Because the only known fate for citrulline is arginine synthesis and the enzymes that catalyze this reaction are widespread among body tissues, we hypothesized that citrulline can be utilized directly by tissues to meet, at least partially, their arginine needs. To test this hypothesis, we used stable and radioactive tracers in conscious, partially nephrectomized (½ and ⅚) and anesthetized acutely kidney-ligated mouse models. Nephrectomy increased plasma citrulline concentration but did not affect citrulline synthesis rates, thus reducing its clearance. Nephrectomy (⅚) reduced the amount of citrulline accounted for as plasma arginine from 88 to 42%. Acute kidney ligation increased the half-life and mean retention time of citrulline. Whereas the rate of citrulline conversion into plasma arginine was reduced, it was not eliminated. In addition, we observed direct utilization of citrulline for arginine synthesis and further incorporation into tissue protein in kidney-ligated mice. These observations indicate that a fraction of the citrulline produced is utilized directly by multiple tissues to meet their arginine needs and that extrarenal sites contribute to plasma arginine. Furthermore, when the interorgan synthesis of arginine is impaired, these extrarenal sites are able to increase their rate of citrulline utilization.

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Section: Chronic Nephrectomy Reduces Clearance Of Citrulline and De Ncontrasting

confidence: 96%

Section: Calculationsmentioning

confidence: 99%

Extrarenal citrulline disposal in mice with impaired renal function

Marini

Didelija

Fiorotto

2014

American Journal of Physiology-Renal Physiology

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“…Previous studies showed that the overexpression of DDAH reduced tissue and plasma levels of ADMA which was associated with an increased production of NO, a reduction in systemic vascular resistance, and reduced atherosclerosis in transgenic mice [ 4 , 5 ]. The DDAH activity also has a protective role in insulin resistance [ 6 , 7 ] and progression of chronic kidney disease, which are both associated with reduced level of ADMA and increased endogenous NO production [ 8 , 9 ]. A reduced expression or pharmacological inhibition of DDAH results in elevated levels of ADMA associated with decreased reaction of NO-mediated vasodilation [ 10 ] which supports the idea that local tissue DDAH activity plays an important role in the maintenance of vascular tone and NOS activity via ADMA production.…”

Section: Introductionmentioning

confidence: 99%

Endogenous Asymmetric Dimethylarginine Pathway in High Altitude Adapted Yaks

Mizuno

Ishizaki

Toga

et al. 2015

BioMed Research International

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Hypoxia-induced and high altitude pulmonary hypertension are a major problem in the mountain areas of the world. The asymmetric methylarginines (ADMA) inhibit nitric oxide (NO) synthesis by competing with L-arginine, and high levels of plasma ADMA predict adverse outcomes in pulmonary hypertension. However, little is known about the regulation of the ADMA-NO pathway in animals adapted to high altitudes. We measured the plasma ADMA concentration, endothelial NO synthase (eNOS), dimethylarginine dimethylaminohydrolases (DDAH) protein expression, and DDAH activities in the lungs from yaks. Although the yaks are hypoxemic, cardiac function and pulmonary arterial pressures are almost normal, and we found decreased DDAH expression and activity in association with reduced plasma ADMA concentrations. The eNOS expression was significantly higher in yaks. These results indicate that augmented endogenous NO activity in yaks through the ADMA-DDAH pathway and eNOS upregulation account for the low pulmonary vascular tone observed in high altitude adapted yaks.

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“…Recent reports have suggested that circulating ADMA is not simply determined by renal clearance or DDAH activities of kidney and liver, but also affected by disposal of other tissue, especially by vascular endothelial cells [24,25]. Even after these results, regulatory mechanisms on circulating ADMA are complex and not fully understood yet, and therefore the relative contributory role of renal DDAH to the circulating level of ADMA in CKD remains elusive.…”

Section: Discussionmentioning

confidence: 99%

Effects of Losartan and Pentoxifylline on Renal Dimethylarginine Dimethylaminohydrolase-1 Expression in Proteinuric Nephropathy

Park

Hyun²,

Ryu³

et al. 2013

Am J Nephrol

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Background/Aims: Circulatory asymmetric dimethylarginine (ADMA) is correlated with proteinuria and endothelial dysfunction in patients with proteinuric renal diseases. However, it is not known whether proteinuria itself affects expression of dimethylarginine dimethylaminohydrolase (DDAH), a degrading enzyme of ADMA, in kidney. The aim of this study is to evaluate the direct effects of losartan and/or pentoxifylline on expression of renal DDAH-1 and its relation to oxidative stress in the setting of albuminuria. Methods: Using NRK52E cells, DDAH-1 mRNA and protein were determined after exposure to albumin with losartan and/or pentoxifylline. Reactive oxygen species (ROS), PKC activity, and NOX-4 mRNA were also measured. In addition, the effect of losartan and/or pentoxifylline on renal expression of DDAH-1 and serum ADMA were evaluated in a rat model of proteinuric nephropathy. Results: Exposure to albumin resulted in increased release of N-acetyl-β-D-glucosaminidase along with an increase of TNF-α, 8-hydroxy-2′-deoxyguanosine, and angiotensin II in NRK52E cells. Losartan and pentoxifylline reversed albumin-induced decrease of DDAH-1 mRNA and protein expression and DDAH-1 activity. The effects of losartan and pentoxifylline on DDAH-1 mRNA were associated with reduction of ROS. In addition, treatment with losartan and pentoxifylline resulted in an attenuated change of renal DDAH-1 protein expression and serum ADMA levels in vivo. Conclusion: DDAH-1 was positively regulated by losartan and pentoxifylline with its antioxidative effect in albumin-exposed renal proximal tubular cells. Combined treatment with losartan and pentoxifylline has a direct beneficial effect on expression of renal DDAH-1, and, thus, at least in part, modulates the circulatory levels of ADMA in proteinuric nephropathy.

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

Cited by 14 publications

References 43 publications

Extrarenal citrulline disposal in mice with impaired renal function

Extrarenal citrulline disposal in mice with impaired renal function

Endogenous Asymmetric Dimethylarginine Pathway in High Altitude Adapted Yaks

Effects of Losartan and Pentoxifylline on Renal Dimethylarginine Dimethylaminohydrolase-1 Expression in Proteinuric Nephropathy

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