L-arginine depletion inhibits glomerular nitric oxide synthesis and exacerbates rat nephrotoxic nephritis

Waddington, Simon; Cook, H. Terence; Reaveley, D. A.; Jansen, A.; Cattell, Victoria

doi:10.1038/ki.1996.158

Cited by 53 publications

(37 citation statements)

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“…Transfection of endothelial cells with arginase II increased L-arginine consumption and reduced NO synthesis 26 and in vivo administration of arginase to experimental animals significantly depleted plasma L-arginine. 32 Arginase II mRNA expression was more than 4-fold higher in preeclamptic than in NP villous tissue; also, protein expression was increased, as documented by immunostaining and Western blot data. In addition, levels of arginase II mRNA in villous tissue inversely correlated with fetal L-arginine concentration.…”

Section: Discussionmentioning

confidence: 86%

l -Arginine Depletion in Preeclampsia Orients Nitric Oxide Synthase Toward Oxidant Species

et al. 2004

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Abstract-Less nitric oxide (NO)-dependent vasodilation and excess formation of reactive oxygen species could explain poor placenta perfusion in preeclampsia, but the pathways involved are unknown. We tested the hypothesis that reduced NO activity and increased oxidative stress in preeclamptic placenta is related to a low bioavailability of L-arginine. Placental endothelial NO synthase (ecNOS) expression (by immunoperoxidase) and activity (by diaphorase and [ 3 H]L-citrulline formation) were comparable in normotensive pregnancy and in preeclampsia, whereas nitrotyrosine staining, a marker of peroxynitrite, was stronger in preeclamptic villi, confirming previously reported data. Oxidative tissue damage was documented in preeclamptic villi by strong 4-hydroxynonenal-lysine staining (by immunoperoxidase), which closely colocalized with nitrotyrosine. Concentration of the NO precursor L-arginine (by HPLC) in umbilical blood and in villous tissue was lower in preeclampsia than in normotensive pregnancy. This was not caused by a defective L-arginine transport, because gene expression of the CAT-1, 4F2hc, and LAT-1 cationic amino acid transporters (by real-time reverse-transcription polymerase chain reaction [RT-PCR]) was normal. Instead, gene expression (by real-time RT-PCR) and protein tissue content (by immunoperoxidase and Western blot) of arginase II-the enzyme that degrades arginine to ornithine-were higher in preeclamptic villi than in normotensive pregnancy. These results provide a biochemical explanation for defective NO activity and increased oxidative stress in preeclamptic placenta. In normal placenta, adequate concentration of L-arginine orients ecNOS toward NO. In preeclampsia, a lower than normal L-arginine concentration caused by arginase II overexpression redirects ecNOS toward peroxynitrite. Key Words: arginine Ⅲ nitric oxide synthase Ⅲ nitrites Ⅲ oxidative stress Ⅲ preeclampsia I n the past few years, evidence has accumulated suggesting that nitric oxide (NO), a potent endothelial-derived vasodilator, might be implicated in gestational vasodilation. 1,2 NO is synthesized from the amino acid L-arginine by a family of enzymes, the NO synthases (NOS). 3 While human placenta does not form inducible NOS (iNOS) or neuronal NOS (nNOS) mRNAs and proteins, 1 the endothelial isoform of NOS (ecNOS) is actually detectable in healthy placenta and is localized to the endothelium of the umbilical cord, chorionic plate, and stem villous vessels. 1 Conceivably, locally formed NO serves to maintain low vascular resistance besides attenuating the action of vasoconstrictors. 1 Besides, ecNOS is localized in villous cytotrophoblasts, 1,4 the specialized epithelial cells that aggregate into cell columns and invade the uterine interstitium and vasculature, anchoring the fetus to the mother and establishing blood flow to the placenta. 5 By virtue of its unique angiogenic/vasculogenic properties, 6,7 locally generated NO may be instrumental to promote this cytotrophoblast endovascular invasion that is an essential feature o...

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Section: Discussionmentioning

confidence: 86%

l -Arginine Depletion in Preeclampsia Orients Nitric Oxide Synthase Toward Oxidant Species

et al. 2004

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“…Arginine also is the precursor of urea, agmatine, and nitric oxide (NO). In past years, many studies have been undertaken that aimed at increasing or decreasing NO production, either by supplementation of arginine or NO donors (6,25,26) or by the administration of nitric oxide synthase (NOS) inhibitors or arginase (5,15,33). In general, the effects of these treatments were conflicting and confusing.…”

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confidence: 99%

“…Previous studies have suggested that systemic NO production is dependent on extracellular arginine supply (2,21) and that reduced arginine availability may impair systemic NO production (2,33). It therefore appears important to regulate arginine availability.…”

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confidence: 99%

“…iNOS is dependent on the extracellular supply of arginine (2,21), and reduced arginine availability may impair systemic NO production (2,33). During conditions of increased arginine utilization, the kidney may increase endogenous arginine production to serve systemic NO production; however, it is well known that Ͻ5% of arginine disposal is used for NO production.…”

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confidence: 99%

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Renal arginine and protein synthesis are increased during early endotoxemia in mice

Hallemeesch

Soeters

Deutz

2002

American Journal of Physiology-Renal Physiology

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Hallemeesch, Marcella M., Peter B. Soeters, and Nicolaas E. P. Deutz. Renal arginine and protein synthesis are increased during early endotoxemia in mice. Am J Physiol Renal Physiol 282: F316-F323, 2002. First published August 21, 2001 10.1152/ajprenal.00039.2001The kidney has an important function in arginine metabolism, because the kidney is the main endogenous source for de novo arginine production from circulating citrulline. In conditions such as sepsis, nitric oxide (NO) production is increased and is dependent on extracellular arginine availability. To elucidate the adaptive role of renal de novo arginine synthesis in a condition of increased NO production, we studied renal arginine metabolism in a mouse model of endotoxemia. Because arginine flux is largely dependent on protein flux, we also measured protein metabolism in mice. Female mice were injected intraperitoneally with lipopolysaccharide; control mice received 0.9% NaCl. Six hours later, renal blood flow was measured with the use of para-aminohippuric acid. Arginine and protein metabolism were studied using organbalance, stable-isotope techniques. Systemic NO production was increased in the endotoxin-treated mice. In addition, renal protein synthesis and de novo arginine production from citrulline were increased. However, no effect on renal NO production was observed. In conclusion, increased renal de novo arginine production may serve to sustain systemic NO production. To our knowledge, it was shown for the first time that renal protein synthesis is enhanced in the early response to endotoxemia. citrulline; kidney; lipopolysaccharide; nitric oxide THE AMINO ACID ARGININE HAS an important role in cellular regeneration, immune function, and protein breakdown and synthesis (7,39). Arginine also is the precursor of urea, agmatine, and nitric oxide (NO). In past years, many studies have been undertaken that aimed at increasing or decreasing NO production, either by supplementation of arginine or NO donors (6,25,26) or by the administration of nitric oxide synthase (NOS) inhibitors or arginase (5, 15,33). In general, the effects of these treatments were conflicting and confusing. More detailed information on local arginine metabolism and NO production may be helpful for an understanding of the effects of arginine supplementation or NOS inhibition.The kidney has an important function in arginine metabolism, because the kidney is the main endogenous source for de novo arginine production (37). Arginine production involves collaboration between the gut and the kidney. Citrulline is produced from glutamine and arginine in the gut and then released into the circulation. The liver does not consume citrulline, which leaves it available for the kidney. In the kidney, citrulline is used for the production of arginine, which, in turn, is released into the circulation (37). The importance of this pathway is illustrated by the fact that arginine becomes an essential amino acid when intestinal citrulline synthesis is inhibited (34).During sepsis and experimental ...

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“…However, proteinuria in acute-phase heterologous nephrotoxic nephritis was exacerbated by L -NMMA infusion, together with increases in elevated glomerular pressure and arteriolar resistance [3]. N-nitro- L -arginine methyl ester ( L -NAME) treatment in passive and active Heymann nephritis also worsened proteinuria [4, 5], as did depletion of the NOS substrate arginine via systemic administration of arginase [6]. The common, and probably complicating, theme in these studies was the use of nonselective inhibitors of NOS isoforms.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Inducible Nitric Oxide Synthase Alters Thy-1 Glomeruonephritis in Rats

Satriano

Lortie²,

Ishizuka³

et al. 2006

Nephron Physiol

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Background/Aims: Inducible nitric oxide (NO) synthase (iNOS) generated NO increases in the early phase of Thy-1 glomerulonephritis concurrently with mesangiolysis and reduction in glomerular filtration rate (GFR). Activation of ornithine decarboxylase (ODC), the rate-limiting enzyme of polyamine biosynthesis, is upregulated to allow mesangial cell proliferation which constitutes the repair phase in this model. Antiproliferative high-output NO generation inhibits proproliferative ODC activity, thereby temporally separating the early ‘bactericidal’ phase from the later ‘growth’ repair phase. Methods: Renal function, ODC protein expression, arginine, ornithine, and polyamines by high-performance liquid chromatography, and histological changes were assessed in rats after induction of Thy-1 nephritis with and without NOS inhibition. Results: Thy-1 significantly reduced the GFR relative to untreated controls. Treatment with a nonspecific NOS inhibitor, but not a selective iNOS inhibitor, further decreased the GFR at day 1. This implys a protective role for constitutive NOS in the early phase of this inflammatory model. Selective iNOS inhibition abrogated increased plasma NO₂/NO₃ levels in Thy-1 glomerulonephritis, but did not significantly reduce mesangiolysis. However, inhibition of iNOS did result in significantly more nuclei/glomerulus during the proliferative phase, increasing the hypercellularity component of this disease model. This correlates with increased levels of polyamines, ornithine, and arginine beyond those observed with Thy-1 administration alone. Conclusions: These studies provide evidence that NO generation from different NOS isoforms can be protective in the temporal course of Thy-1 glomerulonephritis. The finding that iNOS attenuates hypercellularity in the repair phase of this inflammatory model adds cautionary insight in the therapeutic use of selective iNOS inhibition in vivo.

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L-arginine depletion inhibits glomerular nitric oxide synthesis and exacerbates rat nephrotoxic nephritis

Cited by 53 publications

References 18 publications

l -Arginine Depletion in Preeclampsia Orients Nitric Oxide Synthase Toward Oxidant Species

l -Arginine Depletion in Preeclampsia Orients Nitric Oxide Synthase Toward Oxidant Species

Renal arginine and protein synthesis are increased during early endotoxemia in mice

Inhibition of Inducible Nitric Oxide Synthase Alters Thy-1 Glomeruonephritis in Rats

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