Arginase is a major pathway of L-arginine metabolism in nephritic glomeruli

Jansen, A.; Lewis, Simon E.; Cattell, Victoria; Cook, H. Terence

doi:10.1038/ki.1992.394

Cited by 51 publications

(30 citation statements)

References 16 publications

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“…These findings will allow us to evaluate the potential use of iNOS inhibitors in the management of renal damage. A role for iNOS in mediating glomerular damage in models of renal inflammation has also been reported (Cattell et al, 1990;Cook & Sullivan, 1991;Jansen et al, 1992). A weaker protective effect was observed with the non-selective cNOS/iNOS inhibitor L-NMMA or L-NAME.…”

Section: Discussionmentioning

confidence: 83%

Regulation of prostaglandin production by nitric oxide; an in vivo analysis

Salvemini¹,

Settle²,

Masferrer³

et al. 1995

British J Pharmacology

238

126

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1 Endotoxin E. Coli lipopolysaccharide (LPS)-treatment in conscious, restrained rats increased plasma and urinary prostaglandin (PG) and nitric oxide (NO) production. Inducible cyclo-oxygenase (COX-2) and nitric oxide synthase (iNOS) expression accounted for the LPS-induced PG and NO release since the glucocorticoid, dexamethasone inhibited both effects. Thus, LPS (4 mg kg-1) increased the plasma levels of nitrite/nitrate from 14 ± 1 to 84 ± 7 JM within 3 h and this rise was inhibited to 35 ± 1 flM by dexamethasone. Levels of 6-keto PGFI,, in the plasma were below the detection limit of the assay (<0.2 ng ml-'). However, 3 h after the injection of LPS these levels rose to 2.6 ± 0.2 ng ml' and to 0.7 ± 0.01 ng ml' after LPS in rats that received dexamethasone. 2 The induced enzymes were inhibited in vivo with selective COX and NOS inhibitors. Furthermore, NOS inhibitors, that did not affect COX activity in vitro markedly suppressed PG production in the LPS-treated animals. For instance, the LPS-induced increased in plasma nitrite/nitrate and 6-keto PGFIe.at 3 h was decreased to 18 ± 2 iM and 0.5 ± 0.02 ng ml-', 23 ± 1 ilM and 0.7 ± 0.01 ng ml-', 29 ± 2 LLM and 1 ± 0.01 ng ml-' in rats treated with LPS in the presence of the NOS inhibitors NG-monomethyl-Larginine, N'-nitro arginine methyl ester and aminoguanidine, respectively.3 The intravenous infusion of the NO donors sodium nitroprusside (SNP) or glyceryl trinitrate (GTN) increased prostaglandin production in normal animals (for instance urinary PGE2 excretion was increased from 96 ± 10 to 576 ± 12 pg min-' and 400 ± 24 pg min-' in the presence of GTN or SNP respectively). 4 Proteinuria was measured in order to evaluate the roles of NO and PG in renal damage associated with the in vivo injection of LPS. Interestingly, dexamethasone and the NOS inhibitors attenuated proteinuria in the LPS-treated rats. The COX inhibitors had no effect. It therefore appears that NO and not PG contributes to the LPS-induced renal damage; these findings support the potential use of NOS inhibitors in the treatment of renal inflammation. 5 This study demonstrates the regulatory contribution of NO on the in vivo production of prostanoids and suggests that in inflammatory diseases that are driven by both NO and the prostaglandins, NOS inhibitors may act to reduce inflammation by the dual inhibition of cytotoxic NO and pro-inflammatory PG.

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Section: Discussionmentioning

confidence: 83%

Regulation of prostaglandin production by nitric oxide; an in vivo analysis

Salvemini¹,

Settle²,

Masferrer³

et al. 1995

British J Pharmacology

238

126

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“…If this inhibition would occur also in lung arginase, a decreased formation of NO and citrulline would not only limit arginine availability, but also would limit inhibition of arginase, therefore channeling arginine toward urea and ornithine. There is evidence in recent investigations that in some pathophysiologic states, such as glomerulonephritis (45) and wound healing (46), there is a temporal expression of these two different pathways of L-arginine metabolism (Larginine+ornithine pathway and the L -a r g i n i n e j N 0 -citrulline pathway), depending on the pathophysiologic state. We speculate that, although it is possible that the etiology of pulmonary vasoconstriction and remodeling of the pulmonary arteries is perhaps multifactorial, involving growth factors (47), endothelins (48), and nitric oxide (4), a preferential direction of arginine metabolism toward the formation of ornithine and polyamines resulting in smooth muscle proliferation and remodeling of the pulmonary arteries, with a concomitant fall in the activity of the L-arginine-NO-citrulline pathway leading to pulmonary vasoconstriction and hypertension, may contribute to this pathology (Fig.…”

Section: Discussionmentioning

confidence: 99%

Whole Body Arginine Metabolism and Nitric Oxide Synthesis in Newborns with Persistent Pulmonary Hypertension

Castillo

deRojas-Walker

et al. 1995

Pediatr Res

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R A C TDespite the potential relevance of the L-arginine-nitric oxide (NO) pathway in the pathophysiology of pulmonary hypertension, no in vivo studies of the kinetics of arginine and NO have been conducted previously in this population. The terminal guanidino N-atom of L-arginine is the precursor for NO, which is oxidized to the stable inorganic nitrogen oxides, nitrite (NO,-) and nitrate (NO,-). Thus, synthesized NO is detected in serum or urine as NO,-and NO,-. The purpose of this investigation was to compare studies of whole body arginine metabolism twice in nine patients with persistent pulmonary hypertension of the newborn (PPHN), using a primed constant i.v. infusion of ~-[~uanidino-~~N,,5,5~H,]ar~inine and L- [5,5,52~,]leucine, first during acute pulmonary vasoconstriction and again during convalescence, and thereby to characterize quantitative aspects of whole body arginine kinetics and NO production, as estimated from the rate of transfer of the '5~-guanidino-label of arginine to urinary nitrate (ISNO,-). Arginine flux rates were 84.1 ? 8.6 p r n~l -k~. -~h -~ (mean ? SEM) during acute pulmonary hypertension and increased to 125 ? 13.2 ( p < 0.05) during conva-PPHN is an acute vascular maladaptation to extrauterine life, characterized by reactive pulmonary vasoconstriction, causing extrapulmonary shunting of blood across fetal channels and critical hypoxemia. Remodeling of the pulmonary arteries has been observed in some patients with PPHN (1). The etiology of this disorder is uncertain, but a role for altered NO production, a recently discovered key regulator of vascular tone (2-4), Received October 10, 1994; accepted February 27, 1995 Abbreviations PPHN, persistent pulmonary hypertension of the newborn NO, nitric oxide eNOS, nitric oxide synthase AaDO,, alveolo-arterial oxygen gradient ECMO, extracorporeal membrane oxygenation A.P.E., atom percent excess must be considered. NO is produced in the pulmonary and systemic arteries of newborn animals (5) and contributes to the postnatal vasodilation of the pulmonary circulation (6, 7). NO is synthesized in the endothelial cells, through the action of eNOS, and diffuses into subjacent vascular smooth muscle, where it binds to its molecular target, the prosthetic heme group of soluble guanylyl cyclase, forming nitrosyl proteins (8). This process activates guanylyl cyclase, augmenting levels of the second messenger, cGMP (8). Intracellular elevation of cGMP levels activates cGMP-dependent protein kinases, leading to phosphorylation of proteins and inhibition of intracellu-MA 02114. lar calcium release and/or influx through calcium channels.

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“…Elevated arginase activity could limit NO synthesis by reducing L-arginine availability for NOS (17). It has been documented that arginase activity is 5-fold greater than NOS activity and arginase was found to be present in the major pathway of L-arginine metabolism in nephritic glomeruli (18); likewise, it was suggested that while arginase activity increases, NOS activity decreases in the erythrocytes of the patients with chronic renal failure (19). It was also reported that for the mammalian arginase, the Km for …”

Section: Discussionmentioning

confidence: 99%

Effect of Rosuvastatin on Arginase Enzyme Activity and Polyamine Production in Experimental Breast Cancer

Erbas¹,

Bal²,

Çakır³

2015

Balkan Med J

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Breast cancer is still the commonest type of cancer in women. It accounts for about 20% of all cancer-related mortality. Therefore, great medical and scientific efforts are continually invested into understanding the disease's pathology and finding new methods for its early diagnosis, prevention and treatment.In cells, L-arginine is embraced in protein synthesis. Arginine is also used by arginase, arginine decarboxylase, nitric oxide synthases (NOSs) and glycine transaminase. Arginase is a crucial enzyme that is chargeable for nitrogen metabolism. Arginine is its main substrate; from this, urea and L-ornithine are formed (1). There are two types of arginase: Arginase I is cytosolic and mostly found in the liver; it is considered to be primarily liable for the detoxification of ammonia. The other isoenzyme, arginase II, is engaged in ornithine creation. Ornithine is the precursor of some products which take place in cell growth: glutamate, proline and polyamines (spermine, Background: Breast cancer is the most common malignant tumour of women around the world. As a key enzyme of the urea cycle, arginase leads to the formation of urea and ornithine from L-arginine. In the patients with several different cancers, arginase has been found to be higher and reported to be a useful biological marker. Aims: The aim of this study was to investigate the effect of rosuvastatin on serum and cancer tissue arginase enzyme activity, and ornithine and polyamine (putrescine, spermidine, spermine) levels. Study Design: Animal experiment. Methods: In this study, 50 male Balb/c mice were used. Erchlich acid tumour cells were injected into the subcutaneous part of their left foot. The mice were divided into five groups: healthy control group, healthy treatment, tumour control, treatment 1 and treatment 2. Then, 1 mg/kg and 20 mg/kg doses of rosuvastatin were given intraperitoneally. Serum and tissue arginase enzyme activities and tissue ornithine levels were determined spectrophotometrically. HPLC measurement of polyamines were applied. Results: Increased serum arginase activity and polyamine levels were significantly decreased with rosuvastatin treatment. In the tumour tissue, arginase activity and ornithine levels were significantly decreased in treatment groups compared to the tumour group. Tissue polyamine levels also decreased with rosuvastatin treatment. Conclusion:We suggest that rosuvastatin may have some protective effects on breast cancer development as it inhibits arginase enzyme activity and ornithine levels, precursors of polyamines, and also polyamine levels. This protective effect may be through the induction of nitric oxide (NO) production via nitric oxide synthase (NOS). As a promising anticancer agent, the net effects of rosuvastatin in this mechanism should be supported with more advanced studies and new parameters. Keywords: Arginase, breast cancer, ornithine, polyamines, rosuvastatin Copyright 2015 © Trakya University Faculty of Medicine Balkan Med J 201532:89-95

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Arginase is a major pathway of L-arginine metabolism in nephritic glomeruli

Cited by 51 publications

References 16 publications

Regulation of prostaglandin production by nitric oxide; an in vivo analysis

Regulation of prostaglandin production by nitric oxide; an in vivo analysis

Whole Body Arginine Metabolism and Nitric Oxide Synthesis in Newborns with Persistent Pulmonary Hypertension

Effect of Rosuvastatin on Arginase Enzyme Activity and Polyamine Production in Experimental Breast Cancer

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