Arginase in glomerulonephritis
2002; Elsevier BV; Volume: 61; Issue: 3 Linguagem: Inglês
10.1046/j.1523-1755.2002.00236.x
ISSN1523-1755
Autores Tópico(s)Metabolism and Genetic Disorders
ResumoArginase in glomerulonephritis.l-Arginine is converted to nitric oxide and citrulline by the enzyme nitric oxide synthase (NOS). Its in vivo inhibition has led to the revelation of a multitude of diverse, often conflicting functions in the inflammatory melee. l-Arginine is also converted to ornithine and urea by the enzyme arginase as a part of the hepatic urea cycle. However, a more holistic interpretation of the two pathways and the associated metabolism (summarized in Figure 1) has led to its reassessment as a pathologically significant enzyme. This is reflected by the continued increase over the past five years of the number of publications discussing both nitric oxide and arginase. The strong association between inflammation and high arginase and NOS activity is epitomized by immune complex-induced glomerulonephritis and other glomerulonephritides. Arginase is encoded by two recently discovered genes (Arginase I and Arginase II). There is now substantial evidence for an interaction between both arginase isoforms and all three NOS isoforms in pathological situations. This review considers the relationship between Arginases I and II and the inflammation-associated isoform of NOS called NOS II. In particular, it consolidates the current understanding of arginase and associated metabolic pathways, and highlights some of the issues that are often overlooked in such studies. Arginase in glomerulonephritis.l-Arginine is converted to nitric oxide and citrulline by the enzyme nitric oxide synthase (NOS). Its in vivo inhibition has led to the revelation of a multitude of diverse, often conflicting functions in the inflammatory melee. l-Arginine is also converted to ornithine and urea by the enzyme arginase as a part of the hepatic urea cycle. However, a more holistic interpretation of the two pathways and the associated metabolism (summarized in Figure 1) has led to its reassessment as a pathologically significant enzyme. This is reflected by the continued increase over the past five years of the number of publications discussing both nitric oxide and arginase. The strong association between inflammation and high arginase and NOS activity is epitomized by immune complex-induced glomerulonephritis and other glomerulonephritides. Arginase is encoded by two recently discovered genes (Arginase I and Arginase II). There is now substantial evidence for an interaction between both arginase isoforms and all three NOS isoforms in pathological situations. This review considers the relationship between Arginases I and II and the inflammation-associated isoform of NOS called NOS II. In particular, it consolidates the current understanding of arginase and associated metabolic pathways, and highlights some of the issues that are often overlooked in such studies. For example, NOS II and Arginase I have been shown to be up-regulated in glomeruli after induction of heterologous nephrotoxic nephritis1.Waddington S.N. Mosley K. Cook H.T. et al.Arginase AI is upregulated in acute immune complex-induced inflammation.Biochem Biophys Res Commun. 1998; 247: 84-87https://doi.org/10.1006/bbrc.1998.8755Crossref PubMed Scopus (36) Google Scholar. A similar increase in arginase activity and induction of NOS II was observed in in situ glomerulonephritis2.Jansen A. Lewis S. Cattell V. Cook HT: Arginase is a major pathway of arginine metabolism in nephritic glomeruli.Kidney Int. 1992; 42: 1107-1112Abstract Full Text PDF PubMed Scopus (46) Google Scholar, and accelerated nephrotoxic nephritis3.Waddington S.N. Tam F.W.K. et al.Arginase activity is modulated by IL-4 and HOArg in nephritic glomeruli and mesangial cells.Am J Physiol. 1998; 274: F473-F480PubMed Google Scholar. These results were confirmed by Ketteler et al, who studied arginine metabolism in isolated glomeruli from rats with anti-thymocyte serum-induced glomerulonephritis. At day 1, there was a transient maximum of nitrite production, whereas arginase activity was sustained until day 3 of the disease. Ornithine decarboxylase and ornithine aminotransferase, enzymes leading to polyamine and proline production, respectively, were examined. There appeared to be an increase in ornithine decarboxylase at six hours and a delayed increase in ornithine aminotransferase, between days 3 and 213.Waddington S.N. Tam F.W.K. et al.Arginase activity is modulated by IL-4 and HOArg in nephritic glomeruli and mesangial cells.Am J Physiol. 1998; 274: F473-F480PubMed Google Scholar. After injection of lipopolysaccharide (LPS) in rats, NOS II and Arginase I mRNA were co-induced within 12 hours4.Sonoki T. Nagasaki A. Gotoh T. et al.Coinduction of nitric-oxide synthase and arginase I in cultured rat peritoneal macrophages and rat tissues in vivo by lipopolysaccharide.J Biol Chem. 1997; 272: 3689-3693Crossref PubMed Scopus (199) Google Scholar. In contrast, in a model of sepsis, increased expression of NOS II was associated with a loss of Arginase II expression in lung tissue5.Carraway M.S. Piantadosi C.A. Jenkinson C.P. Huang Y-C.T. Differential expression of arginase and iNOS in the lung and sepsis.Exp Lung Res. 1998; 24: 253-288Crossref PubMed Scopus (49) Google Scholar. These pathways have been shown to inhibit each other at multiple levels, including substrate competition and protein and mRNA stability and expression. Glomeruli were isolated from normal rats and nephritic rats four days after the induction of accelerated nephrotoxic nephritis. Addition of the NOS inhibitor NG-monomethyl-l-arginine (L-NMMA) substantially increased metabolism of arginine by arginase over the 48-hour period of culture6.Waddington S.N. Tam F.W.K. Cook H.T. Cattell V. Arginase activity is modulated by IL-4 and HOArg in nephritic glomeruli and mesangial cells.Am J Physiol. 1998; 274: F473-F480PubMed Google Scholar. Limitation of l-arginine flux through the arginase pathway by NOS is likely the result of two independent mechanisms. The first is competition for substrate, discussed later. The second is inhibition of arginase by Nω-hydroxy-l-arginine, an intermediate in the conversion of arginine to NO. This has been shown to be secreted into the culture supernatant of LPS-stimulated rabbit alveolar macrophages and has been shown to increase from 4 to 16 μmol/L in the plasma of LPS-treated rats7.Hecker M. Nematholahi H. Hey C. et al.Inhibition of arginase by N-hydroxyl-L-arginine in alveolar macrophages: Implications for the utilisation of L-arginine for nitric oxide synthesis.FEBS Lett. 1995; 359: 251-254Abstract Full Text PDF PubMed Scopus (110) Google Scholar. In 1994 Boucher and colleagues demonstrated potent inhibition of macrophage arginase by Nω-hydroxy-l-arginine8.Boucher J-L. Custot J. Vadon S. et al.Nω-Hydroxy-L-arginine, an intermediate in the L-arginine to nitric oxide pathway, is a strong inhibitor of liver and macrophage arginase.Biochem Biophys Res Commun. 1994; 203: 1614-1621Crossref PubMed Scopus (144) Google Scholar. This compound also inhibited arginase activity in nephritic glomeruli and in stimulated mesangial cells6.Waddington S.N. Tam F.W.K. Cook H.T. Cattell V. Arginase activity is modulated by IL-4 and HOArg in nephritic glomeruli and mesangial cells.Am J Physiol. 1998; 274: F473-F480PubMed Google Scholar. Another possible mechanism by which NOS activity might affect arginase activity is through the accumulation of nitrite, a breakdown product of NO. Hrabák, Bajor and Temesi demonstrated significant inhibition of inducible nitric oxide synthase (iNOS) in macrophage lysates, but not whole cells, by nitrite, with a Km of 4.9 mmol/L9.Hrabák A. Bajor T. Temesi Á Comparison of substrate and inhibitor specificity of arginase and nitric oxide (NO) synthase for arginine analogues and related compounds in murine and rat macrophages.Biochem Biophys Res Commun. 1994; 198: 206-212https://doi.org/10.1006/bbrc.1994.1029Crossref PubMed Scopus (85) Google Scholar. Evidence that arginase could inhibit the cytotoxic effects of macrophages via NO was first provided by Hibbs, Vavrin and Taintor11.Hibbs J.B. Vavrin Z. Taintor R.R. L-arginine is required for expression of the activated macrophage effector mechanism causing selective metabolic inhibition in target cells.J Immunol. 1987; 138: 550-565PubMed Google Scholar. A similar effect was seen in glomerular cultures. NO is generated by nephritic glomeruli isolated 24 hours after induction of accelerated nephrotoxic nephritis; the addition of arginase to these cultures completely abrogated its production12.Waddington S. Cook H.T. Reaveley D. et al.L-Arginine depletion inhibits glomerular nitric oxide synthesis and exacerbates rat nephrotoxic nephritis.Kidney Int. 1996; 49: 1090-1096Abstract Full Text PDF PubMed Scopus (54) Google Scholar. The Km of arginase for l-arginine is reported to be around 7 to 18 mmol/L13.Kaysen G.A. Strecker H.J. Purification and properties of arginase of rat kidney.Biochem J. 1973; 133: 779-788Crossref PubMed Scopus (123) Google Scholar, whereas that of iNOS is 3 to 9 μmol/L and 130 μmol/L for purified and intact macrophage enzyme activity, respectively14.Stuehr D.J. Kwon N.S. Nathan C.F. et al.Nω-hydroxy-L-arginine is an intermediate in the biosynthesis of nitric oxide from L-arginine.J Biol Chem. 1991; 266: 6259-6263Abstract Full Text PDF PubMed Google Scholar, 15.Hrabák A. Bajor T. Temesi Á Computer-aided comparison of the inhibition of arginase and nitric oxide synthase in macrophages by amino acids not related to arginine.Comp Biochem Physiol. 1996; 113B: 375-381Crossref Scopus (22) Google Scholar, 16.Iyengar R. Stuehr D.J. Marletta M.A. Macrophage synthesis of nitrite, nitrate and N-nitrosoamines: Precursors and role of the respiratory burst.Proc Natl Acad Sci USA. 1987; 84: 6369-6373Crossref PubMed Scopus (614) Google Scholar. The concentration of arginine in rat plasma is around 250 μmol/L, and therefore, ornithine production by arginase will be affected by variations around this level, whereas the arginine concentration should, in theory, drop considerably before NO production is affected17.Noeh F.M. Wenzel A. Harris N. et al.The effects of arginine administration on the levels of arginine, other amino acids and related amino compounds in the plasma, heart, aorta, vena cava and pancreas of the rat.Life Sci. 1996; 58: 131-138Crossref Scopus (18) Google Scholar. Modolell and colleagues provided evidence supporting this statement18.Modolell M. Corraliza I.M. Link F. et al.Reciprocal regulation of the nitric oxide synthase/arginase balance in mouse bone marrow-derived macrophages by Th1 and Th2 cytokines.Eur J Immunol. 1995; 25: 1101-1104Crossref PubMed Scopus (445) Google Scholar. Mouse bone marrow-derived macrophages were stimulated with interleukin-4 (IL-4) for 24 hours, after which LPS was added and the culture continued for a further 24 hours. Cells cultured in medium containing 400 μmol/L arginine had large amounts of arginase but did not generate NO in response to LPS, in contrast to high NO output in 2000 μmol/L. The authors concluded that arginase was depriving NOS of its substrate18.Modolell M. Corraliza I.M. Link F. et al.Reciprocal regulation of the nitric oxide synthase/arginase balance in mouse bone marrow-derived macrophages by Th1 and Th2 cytokines.Eur J Immunol. 1995; 25: 1101-1104Crossref PubMed Scopus (445) Google Scholar. Corroborative observations were made by Chang, Liao and Kuo, who examined these enzyme interactions in J774A.1 mouse macrophages19.Chang C-I. Liao J.C. Kuo L. Arginase modulates nitric oxide production in activated macrophages.Am J Physiol. 1998; 274: H342-H348PubMed Google Scholar. Cells were cultured for 12 hours in different concentrations of l-arginine. The arginase inhibitor l-norvaline increased NO production by 55% and 28% at 0.05 mmol/L and 0.1 mmol/L l-arginine, respectively. Outside this range of arginine concentrations, l-norvaline had no effect. Recently, elegant experiments have been performed using gene delivery technology. Endothelial cells transfected with Arginase I or Arginase II had significantly lower NO production20.Li H. Meininger C.J. Hawker Jr., J.R. et al.Regulatory role of arginase I and II in nitric oxide, polyamine, and proline syntheses in endothelial cells.Am J Physiol Endocrinol Metab. 2001; 280: E75-E82PubMed Google Scholar. Macrophages transfected with Arginase promoted growth of breast tumor cells in co-culture systems. This effect was down-regulated by the arginase inhibitor l-norvaline21.Chang C.I. Liao J.C. Kuo L. Macrophage arginase promotes tumor cell growth and suppresses nitric oxide-mediated tumor cytotoxicity.Cancer Res. 2001; 61: 1100-1106PubMed Google Scholar. In contrast, Arginase I transfection of RAW 264.7 macrophages increased the efferent pathways but did not affect NO production22.Kepka-Lenhart D. Mistry S.K. Wu G. Morris Jr., S.M. Arginase I: A limiting factor for nitric oxide and polyamine synthesis by activated macrophages?.Am J Physiol (Regul Integr Comp Physiol). 2000; 279: R2237-R2242PubMed Google Scholar. There is also some in vivo evidence for inhibition of NO production by arginase. For example, diabetic tissue in the corpus cavernosum had reduced ability to convert l-arginine to l-citrulline. This was reversed by addition of the arginase inhibitor 2(S)-amino-6-boronhexanoic acid (ABH)23.Bivalacqua T.J. Hellstrom W.J. Kadowitz P.J. Champion H.C. Increased expression of arginase II in human diabetic corpus cavernosum: In diabetic-associated erectile dysfunction.Biochem Biophys Res Commun. 2001; 283: 923-927Crossref PubMed Scopus (182) Google Scholar. In a model of experimental trypanosomiasis, macrophages from infected mice have increased arginase activity. Addition of arginase inhibitors restored trypanosome killing in vitro. Injection of arginine into the peritoneal cavity of infected mice increased NO production and parasite killing, an effect reversed by addition of L-NMMA24.Gobert A.P. Daulouede S. Lepoivre M. et al.L-Arginine availability modulates local nitric oxide production and parasite killing in experimental trypanosomiasis.Infect Immun. 2000; 68: 4653-4657Crossref PubMed Scopus (132) Google Scholar. An additional mechanism by which arginase activity inhibits NO production is through urea generation. NO production in RAW 264.7 macrophages was found to be inhibited by 10 mmol/L urea, a concentration similar to that found in uremic humans25.Prabhakar S.S. Zeballos G.A. Montoya-Zavala M. Leonard C. Urea inhibits nitric oxide synthase in macrophage cell line.Am J Physiol. 1997; 273: C1882-C1888PubMed Google Scholar. Several other mechanisms of cross-inhibition have been described. NO has been shown to inhibit ornithine decarboxylase in the MCT kidney tubule cell line26.Satriano J. Ishizuka S. Archer D.C. et al.Regulation of intracellular polyamine biosynthesis and transport by NO and cytokines TNF-alpha and IFN-gamma.Am J Physiol. 1999; 276: C892-C899PubMed Google Scholar and in vascular smooth muscle cells27.Ignarro L.J. Buga G.M. Wei L.H. et al.Role of the arginine-nitric oxide pathway in the regulation of vascular smooth muscle cell proliferation.Proc Natl Acad Sci USA. 2001; 98: 4202-4208Crossref PubMed Scopus (275) Google Scholar. Inactivation of ornithine decarboxylase has been shown to occur by specific S-nitrosylation of the enzyme28.Bauer P.M. Buga G.M. Fukuto J.M. et al.Nitric oxide inhibits ornithine decarboxylase via S-nitrosylation of cysteine 360 in the active site of the enzyme.J Biol Chem. 2001; 276: 34458-34464Crossref PubMed Scopus (103) Google Scholar. Agmatine has been shown to attenuate polyamine synthesis by inhibition of ornithine decarboxylase and also by suppression of the putrescine transporter. Agmatine aldehyde, a metabolite of agmatine, has been shown to be an inhibitor of iNOS in vitro and in vivo. It is likely that these effects are responsible for the inhibition of cell proliferation and improvement in renal function in thymocyte-1 (Thy-1) glomerulonephritis29.Ishizuka S. Cunard R. Poucell-Hatton S. et al.Agmatine inhibits cell proliferation and improves renal function in anti-thy-1 glomerulonephritis.J Am Soc Nephrol. 2000; 11: 2256-2264PubMed Google Scholar. Conversely, polyamines have been shown to inhibit NO production. Szabó and colleagues studied the affect of polyamines and polyamine derivatives on NO production in LPS-stimulated J774.2 macrophages finding that, in order of decreasing potency, spermine, spermidine, putrescine and cadaverine inhibited nitrite production in culture. The inhibitory action of polyamines on iNOS appeared to depend on the presence of spermine oxidase30.Szabó C. Southan G.J. Thiemerman C. Vane J. The mechanism of the inhibitory effect of polyamines on the induction of nitric oxide synthase: Role of aldehyde metabolites.Br J Pharmacol. 1994; 113: 757-766Crossref PubMed Scopus (57) Google Scholar. Hrabák and colleagues examined the effect of various inhibitors on iNOS activity in rat macrophage lysates15.Hrabák A. Bajor T. Temesi Á Computer-aided comparison of the inhibition of arginase and nitric oxide synthase in macrophages by amino acids not related to arginine.Comp Biochem Physiol. 1996; 113B: 375-381Crossref Scopus (22) Google Scholar. Putrescine inhibited iNOS activity with a Ki of 0.7 mmol/L; l-ornithine was also a weak inhibitor. Blachier, Mignon and Soubrane analyzed iNOS activity in homogenates of livers from rats given LPS31.Blachier F. Mignon A. Soubrane O. Polyamines inhibit lipopolysaccharide-induced nitric oxide synthase activity in rat liver cytosol.Nitric Biol Chem. 1997; 1: 268-272Crossref PubMed Scopus (24) Google Scholar. NO production was significantly inhibited by spermine at 150 μmol/L and 500 μmol/L, but by putrescine and spermidine only at the higher concentration. Sooranna and Das showed that putrescine significantly inhibited nitrite production by cultures of the choriocarcinoma cell line BeWo32.Sooranna S.R. Das I. The inter-relationship between polyamines and the L-arginine nitric oxide pathway in the human placenta.Biochem Biophys Res Commun. 1995; 212: 229-234Crossref PubMed Scopus (20) Google Scholar. Many studies have provided circumstantial evidence that arginase activity may be rate-limiting for the production of proline and polyamines. In a physiological context, up-regulation of Arginase II was found to coincide with development of connective tissue (rich in proline) in Xenopus laevis33.Patterton D. Shi Y-B. Thyroid hormone-dependent differential regulation of multiple arginase genes during amphibian metamorphosis.J Biol Chem. 1994; 269: 25328-25334Abstract Full Text PDF PubMed Google Scholar. In the lactating mammary gland, a concerted increase in arginase, ornithine aminotransferase and ornithine decarboxylase was consistent with the increased production of proline and polyamines34.Russell D.H. McVicker T.A. Polyamine biogenesis in the rat mammary gland during pregnancy and lactation.Biochem J. 1972; 130: 71-76Crossref PubMed Scopus (82) Google Scholar,35.Yip M.C. Knox W.E. Function of arginase in lactating mammary gland.Biochem J. 1972; 127: 893-899Crossref PubMed Scopus (82) Google Scholar. A pathological up-regulation of these three enzymes also was observed in anti-thymocyte serum-induced glomerulonephritis3.Waddington S.N. Tam F.W.K. et al.Arginase activity is modulated by IL-4 and HOArg in nephritic glomeruli and mesangial cells.Am J Physiol. 1998; 274: F473-F480PubMed Google Scholar. Harder evidence has been provided by in vitro studies. Transfecting RAW cells with Arginase I increased polyamine synthesis22.Kepka-Lenhart D. Mistry S.K. Wu G. Morris Jr., S.M. Arginase I: A limiting factor for nitric oxide and polyamine synthesis by activated macrophages?.Am J Physiol (Regul Integr Comp Physiol). 2000; 279: R2237-R2242PubMed Google Scholar (with no effect on NO). Transfecting endothelial cells with Arginase I and Arginase II increased proline and polyamine synthesis and decreased NO production20.Li H. Meininger C.J. Hawker Jr., J.R. et al.Regulatory role of arginase I and II in nitric oxide, polyamine, and proline syntheses in endothelial cells.Am J Physiol Endocrinol Metab. 2001; 280: E75-E82PubMed Google Scholar. In a similar study, transfecting vascular smooth muscle cells with Arginase I or treating them with IL-4 resulted in increased urea and polyamine production and cellular proliferation27.Ignarro L.J. Buga G.M. Wei L.H. et al.Role of the arginine-nitric oxide pathway in the regulation of vascular smooth muscle cell proliferation.Proc Natl Acad Sci USA. 2001; 98: 4202-4208Crossref PubMed Scopus (275) Google Scholar. The transforming growth factor-β (TGF-β)–induced increase in putrescine and l-proline generation by vascular smooth muscle cells were profoundly inhibited by the arginase inhibitor HOArg36.Durante W. Liao L. Reyna S.V. et al.Transforming growth factor-beta(1) stimulates L-arginine transport and metabolism in vascular smooth muscle cells: Role in polyamine and collagen synthesis.Circulation. 2001; 103: 1121-1127Crossref PubMed Scopus (114) Google Scholar. Buga and colleagues demonstrated that inhibition of arginase by HOArg retarded Caco-2 tumor cell proliferation. Since this effect was reversed by the addition of ornithine, putrescine, spermidine or spermine, arginase appeared to be required by these cells to synthesize polyamines for optimal cell growth37.Buga G.M. Wei L.H. Bauer P.M. et al.NG-hydroxy-L-arginine and nitric oxide inhibit Caco-2 tumor cell proliferation by distinct mechanisms.Am J Physiol. 1998; 275: R1256-R1264PubMed Google Scholar. Durante et al demonstrated that the polar phospholipid lysophosphatidylcholine increases arginase activity, arginine uptake and putrescine production of smooth muscle. The arginase inhibitor HOArg was shown to strongly inhibit putrescine production in cells38.Durante W. Liao L. Peyton K.J. Schafer A.I. Lysophosphatidylcholine regulates cationic amino acid transport and metabolism in vascular smooth muscle cells.J Biol Chem. 1997; 272: 30154-30159Crossref PubMed Scopus (43) Google Scholar. Albina and colleagues first demonstrated temporal variation in the activity of NOS II and arginase in a rat wound model of implanted polyvinyl sponges. Over the first 12 hours, NOS activity prevailed. From 12 hours to three days, the NOS activity rapidly decreased and the arginine concentration rose. From three to ten days, the arginine concentration fell slowly as wound fluid arginase increased. Disappearance of NOS activity by three days could not be explained by a dearth of arginine, as culture of sponges in high-arginine medium did not elicit nitrite or citrulline synthesis39.Albina J.E. Mills C.D. Henry W.L. Caldwell M.D. Temporal expression of different pathways of L-arginine metabolism in healing wounds.J Immunol. 1990; 144: 3877-3880PubMed Google Scholar,40.Albina J.E. Caldwell M.D. Henry W.L. Mills C.D. Regulation of macrophage functions by L-arginine.J Exp Med. 1989; 169: 1021-1029Crossref PubMed Scopus (142) Google Scholar. Cook and co-workers reported a similar pattern of enzyme activity41.Cook H.T. Jansen A. Lewis S. et al.Arginine metabolism in experimental glomerulonephritis: interaction between nitric oxide synthase and arginase.Am J Physiol. 1994; 267: F646-F653PubMed Google Scholar. Glomeruli were isolated from the kidneys of rats with acute in situ glomerulonephritis. NOS II activity was induced and arginase activity was increased in nephritic glomeruli at days 1, 4 and 7, compared to normal glomeruli. Whereas the greatest NOS activity was at 24 hours, arginase activity peaked at four days; the activity of both fell rapidly from four to seven days. These results were confirmed by Ketteler et al, who studied arginine metabolism in isolated glomeruli from rats with anti-thymocyte serum-induced glomerulonephritis3.Waddington S.N. Tam F.W.K. et al.Arginase activity is modulated by IL-4 and HOArg in nephritic glomeruli and mesangial cells.Am J Physiol. 1998; 274: F473-F480PubMed Google Scholar. At day 1, there was a transient maximum of nitrite production, whereas arginase activity was sustained until day 3 of the disease. Ornithine decarboxylase and ornithine aminotransferase, enzymes leading to polyamine and proline production, respectively, were examined. There appeared to be an increase in ornithine decarboxylase at six hours and a delayed increase in ornithine aminotransferase between days 3 and 21. The prevailing view is that NOS II and arginase characterize, and are inherent to, distinct phases of the inflammatory process. Early flux of arginine through NOS II is associated with cytotoxicity, promotion of apoptosis42.Chung H.T. Pae H.O. Choi B.M. et al.Nitric oxide as a bioregulator of apoptosis.Biochem Biophys Res Commun. 2001; 282: 1075-1079Crossref PubMed Scopus (445) Google Scholar and nitrosylation of structural components including basement membrane. In the aforementioned studies on implanted sponge models, the authors proposed that NOS activity, probably from neutrophils, would contribute to microbiostasis and vasodilation in the early wound39.Albina J.E. Mills C.D. Henry W.L. Caldwell M.D. Temporal expression of different pathways of L-arginine metabolism in healing wounds.J Immunol. 1990; 144: 3877-3880PubMed Google Scholar,40.Albina J.E. Caldwell M.D. Henry W.L. Mills C.D. Regulation of macrophage functions by L-arginine.J Exp Med. 1989; 169: 1021-1029Crossref PubMed Scopus (142) Google Scholar. In contrast, the delayed flux of arginine through arginase is linked to cell proliferation via polyamine synthesis27.Ignarro L.J. Buga G.M. Wei L.H. et al.Role of the arginine-nitric oxide pathway in the regulation of vascular smooth muscle cell proliferation.Proc Natl Acad Sci USA. 2001; 98: 4202-4208Crossref PubMed Scopus (275) Google Scholar,43.Boutard V. Havouis R. Fouqueray B. et al.Transforming growth factor beta stimulates arginase activity in macrophages.J Immunol. 1995; 155: 2077-2084PubMed Google Scholar, collagen synthesis36.Durante W. Liao L. Reyna S.V. et al.Transforming growth factor-beta(1) stimulates L-arginine transport and metabolism in vascular smooth muscle cells: Role in polyamine and collagen synthesis.Circulation. 2001; 103: 1121-1127Crossref PubMed Scopus (114) Google Scholar,44.Durante W. Liao L. Reyna S.V. et al.Physiological cyclic stretch directs L-arginine transport and metabolism to collagen synthesis in vascular smooth muscle.FASEB J. 2000; 14: 1775-1783Crossref PubMed Scopus (62) Google Scholar and moderation of apoptosis45.Brüne B. Hartzell P. Nicotera P. Orrenius S. Spermine prevents endonuclease activation and apoptosis in thymocytes.Exp Cell Res. 1991; 195: 323-329Crossref PubMed Scopus (186) Google Scholar. For example, TGF-β increases fibrosis and wound repair as well as orchestrates the up-regulation of a whole armature of arginine metabolism including arginase, ornithine aminotransferase and collagen36.Durante W. Liao L. Reyna S.V. et al.Transforming growth factor-beta(1) stimulates L-arginine transport and metabolism in vascular smooth muscle cells: Role in polyamine and collagen synthesis.Circulation. 2001; 103: 1121-1127Crossref PubMed Scopus (114) Google Scholar. In contrast, TGF-β down-regulates iNOS induction in rat renal mesangial cells46.Pfeilschifter J. Vosbeck K. Transforming growth factor β2 inhibits the interleukin 1β- and tumour necrosis factor α-induction of nitric oxide synthase in rat renal mesangial cells.Biochem Biophys Res Commun. 1991; 175: 372-379Crossref PubMed Scopus (161) Google Scholar as well as many other cell types. Recently, it has been suggested that NOS II and arginase activity are intrinsic to the T-helper 1 and 2 cell (Th1 and Th2) immune responses, respectively. As the Th1/Th2 dichotomy of murine CD4+ T cells became more widely accepted, interest in regulation of arginine metabolism by cytokines secreted by these subsets increased. Th1 cells produce interferon-γ (IFN-γ), whereas Th2 cells generate IL-4 and IL-10. Following evidence that IL-4 and IL-10 strongly suppressed the induction of iNOS47.Cunha F.Q. Moncada S. Liew F.Y. Interleukin-10 (IL-10) inhibits the induction of nitric oxide synthase by interferon-γ in murine macrophages.Biochem Biophys Res Commun. 1992; 182: 1155-1159Crossref PubMed Scopus (359) Google Scholar,48.Liew F.Y. Li Y. Severn A. et al.A possible novel pathway of regulation by murine T helper type-2 (Th2) cells of a Th1 cell activity via modulation of the induction of nitric oxide synthase on macrophages.Eur J Immunol. 1991; 21: 2489-2494Crossref PubMed Scopus (211) Google Scholar, Modolell and Corraliza demonstrated their effect on arginase activity in cell lysates of bone marrow-derived murine macrophages18.Modolell M. Corraliza I.M. Link F. et al.Reciprocal regulation of the nitric oxide synthase/arginase balance in mouse bone marrow-derived macrophages by Th1 and Th2 cytokines.Eur J Immunol. 1995; 25: 1101-1104Crossref PubMed Scopus (445) Google Scholar,49.Corraliza I.M. Soler G. Eichmann K. Modolell M. Arginase induction by suppressors of nitric oxide synthesis (IL-4, IL-10, PGE2) in murine bone-marrow-derived macrophages.Biochem Biophys Res Commun. 1995; 206: 667-673https://doi.org/10.1006/bbrc.1995.1094Crossref PubMed Scopus (285) Google Scholar. They demonstrated an increase in cellular arginase content when macrophages were cultured with IL-4 and IL-10. These results lent credibility to the hypothesis that Th2 cytokines were not simply reducing macrophage activation but inducing an alternative phenotype. In subsequent studies, macrophages were cultured with Th1 or Th2 cell clones, or with in vitro polarized Th1 or Th2 cells. Both systems showed the same pattern; Th1 and Th2 cells exclusively induced iNOS and arginase, respectively. Arginase was induced to a far greater extent than with Th2 cytokines alone, and supernatant from Th2 cells also induced arginase. Antibodies against IL-4 and IL-10 substantially abrogated the stimulatory effect of the supernatant on arginase activity50.Munder M. Eichmann K. Modolell M. Alternative metabolic states in murine macrophages reflected by the nitric oxide synthase/arginase balance: competitive regulation by CD4+ T cells correlates with Th1/Th2 phenotype.J Immunol. 1998; 160: 5347-5354PubMed Google Scholar. Recently, it has been shown that this phenotypic dichotomy also extends to murine macrophages independently of the effect of T- or B-lymphocytes. C57Bl/6 mice and BALB/c mice are prototypical Th1 and Th2 strains, respectively; macrophages from C57Bl/6 NUDE or SCID mice and BALB/c NUDE or SCID mice demonstrated their respective Th1 and Th2 phenotypes even in the absence of T or B lymphocytes51.Mills C.D. Kincaid K. Alt J.M. et al.M-1/M-2 macrophages and the Th1/Th2 paradigm.J Immunol. 2000; 164: 6166-6173Crossref PubMed Scopus (1613) Google Scholar. We have observed similar characteristics in isolated glomeruli and mesangial cells. Four days after induction of accelerated nephrotoxic nephritis, addition of IL-4 caused a large increase in arginase activity in glomerular cultures independent of the profound decrease in NOS activity over the 48-hour culture period6.Waddington S.N. Tam F.W.K. Cook H.T. Cattell V. Arginase activity is modulated by IL-4 and HOArg in nephritic glomeruli and mesangial cells.Am J Physiol. 1998; 274: F473-F480PubMed Google Scholar. The same observations were made on glomeruli isolated seven days after the induction of disease (unpublished data). When isolated mesangial cells were stimulated with a combination of cyclic adenosine 3′,5′-monophosphate (cAMP) and IL-1β, IL-4 exerted the same effect of independently increasing arginase activity and inhibiting NOS activity. This was accompanied by an increase in cell lysate arginase activity6.Waddington S.N. Tam F.W.K. Cook H.T. Cattell V. Arginase activity is modulated by IL-4 and HOArg in nephritic glomeruli and mesangial cells.Am J Physiol. 1998; 274: F473-F480PubMed Google Scholar. iNOS and Arginase I mRNA were undetectable in unstimulated glomeruli whereas Arginase II mRNA was detectable. iNOS and Arginase I mRNA were induced by the cAMP agonist cholera toxin. Addition of IL-4 increased expression of Arginase I mRNA and abolished expression of iNOS mRNA1.Waddington S.N. Mosley K. Cook H.T. et al.Arginase AI is upregulated in acute immune complex-induced inflammation.Biochem Biophys Res Commun. 1998; 247: 84-87https://doi.org/10.1006/bbrc.1998.8755Crossref PubMed Scopus (36) Google Scholar. There are several issues that often have been omitted from discussion in studies on arginine metabolism, especially in in vivo models. There are three separate points to consider. The first is that local inflammation may lead to increased arginase activity elsewhere. For example, examination of the spleens of mice 12 to 48 hours following surgical trauma revealed increased Arginase I mRNA and protein expression and arginase activity with no effect on Arginase II or NOS II mRNA52.Bernard A.C. Mistry S.K. Morris Jr., S.M. et al.Alterations in arginine metabolic enzymes in trauma.Shock. 2001; 15: 215-219Crossref PubMed Scopus (55) Google Scholar. The same group also observed an increase in renal arginase activity53.Ochoa J.B. Bernard A.C. Mistry S.K. et al.Trauma increases extrahepatic arginase activity.Surgery. 2000; 127: 419-426Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar. The second point pertains to the effect of arginase on immune function at sites distal to the site of inflammation. There is conflicting evidence suggesting that arginase can both inhibit54.Huang M-H. Yang C-C. Wang S-R. Inhibition of lymphocyte proliferation by liver arginase.Life Sci. 1992; 51: 1725-1730Crossref PubMed Scopus (10) Google Scholar and promote55.Klein D. Morris D.R. Increased arginase activity during lymphocyte mitogenesis.Biochem Biophys Res Commun. 1978; 81: 199-204Crossref PubMed Scopus (35) Google Scholar lymphocyte proliferation. Häcker-Shahin and Dröge injected spleen cells from one strain of mouse into the peritoneal cavity of another56.Häcker-Shahin B. Dröge W. Putrescine and its biosynthetic precursor L-ornithine augment the in vivo immunisation against minor histocompatibility antigens and syngeneic tumour cells.Cell Immunol. 1986; 99: 434-443Crossref PubMed Scopus (4) Google Scholar. Spleen cells were isolated from these responder mice and tested for their immunological response to spleen cells of the donor strain (mixed leukocyte reaction). Both putrescine and ornithine augmented the immunogenicity of the cells to the same extent. Therefore, independently of the local inflammation, the systemic immune response may be subject to regulation by arginine concentrations. This point should be considered when systemically administering compounds that modulate activity of arginine-associated enzymes. This leads to the third point, that the sum of systemic activity of arginase and other arginine-associated enzymes will influence plasma amino acid levels. For example, one day after induction of accelerated nephrotoxic nephritis, plasma arginine levels were significantly reduced compared to normal rats12.Waddington S. Cook H.T. Reaveley D. et al.L-Arginine depletion inhibits glomerular nitric oxide synthesis and exacerbates rat nephrotoxic nephritis.Kidney Int. 1996; 49: 1090-1096Abstract Full Text PDF PubMed Scopus (54) Google Scholar. These concentrations are likely to affect the concentrations at the inflammatory site as well as in distal organs. These enzymes, by virtue of their metabolic proximity, act on molecules possessing similar structural characteristics. For example, the NOS inhibitors L-NIO and L-NMMA inhibit uptake of arginine in endothelial cells57.Bogle R. Moncada S. Pearson J.D. Mann G. Identification of inhibitors of nitric oxide synthase that do not interact with the endothelial cell L-arginine transport.Br J Pharmacol. 1992; 105: 768-770Crossref PubMed Scopus (152) Google Scholar since they are transported by the same cationic y+ transporter system as l-arginine58.Baydoun A.R. Mann G.E. Selective targeting of nitric oxide synthase inhibitors to system y+ in activated macrophages.Biochem Biophys Res Commun. 1994; 200: 726-731Crossref PubMed Scopus (72) Google Scholar. A similar effect was demonstrated in rat renal brush border membrane vesicles59.Edwards R.M. Stack E.J. Trizna W. Interaction of L-arginine analogs with L-arginine uptake in rat renal brush border membrane vesicles.J Pharmacol Exp Ther. 1998; 285: 1019-1022PubMed Google Scholar. L-NMMA also was shown to inhibit arginase activity in rat macrophages, most likely by inhibition of arginine uptake60.Keller R. Keist R. Klauser S. Schweiger A. The macrophage response to bacteria: Flow of L-arginine through the nitric oxide and urea pathways and induction of tumoricidal activity.Biochem Biophys Res Commun. 1991; 177: 821-827Crossref PubMed Scopus (24) Google Scholar. α-Difluoromethylornithine (DFMO) is considered to be a potent ornithine decarboxylase inhibitor, however, it also has been shown to inhibit arginase activity61.Selamnia M. Mayeur C. Robert V. Blachier F. α-Difluoromethylornithine (DFMO) as a potent arginase activity inhibitor in human colon carcinoma cells.Biochem Pharmacol. 1998; 55: 1241-1245Crossref PubMed Scopus (44) Google Scholar. Many novel inhibitors of arginase and associated enzymes have not been rigorously tested on their metabolic neighbors, upon which they may be having inhibitory effects or even acting as substrates. This is actually a corollary of the points made in the second and third sections of this review regarding cross-inhibition and modulation of efferent pathways. As discussed earlier, experiments have clearly demonstrated this phenomenon in vitro, yet the knowledge derived from these observations is not yet rigorously applied to interpretation of in vivo experiments. For example, numerous studies administering the NOS inhibitors L-NAME and L-NIL have interpreted the results solely in the context of NO inhibition without reference to the possible consequences of increasing ornithine, polyamines, proline or agmatine formation. A similarly naïve interpretation was made of the results following NOS inhibition using systemic arginase in accelerated nephrotoxic nephritis12.Waddington S. Cook H.T. Reaveley D. et al.L-Arginine depletion inhibits glomerular nitric oxide synthesis and exacerbates rat nephrotoxic nephritis.Kidney Int. 1996; 49: 1090-1096Abstract Full Text PDF PubMed Scopus (54) Google Scholar. This concern should be addressed as more advanced methods of modulating arginine metabolism become available. Although there is simultaneous up-regulation of several enzymes along a metabolic pathway, not all of these enzymes necessarily contribute to the pathological process in vivo. For example, although ornithine decarboxylase (ODC) has been shown to be important for mesangial cell proliferation in vitro and that ODC is increased in Thy 1 glomerulonephritis, Ketteler showed that complete ODC inhibition has no effect62.Ketteler M. Westenfeld R. Gawlik A. et al.Acute glomerular upregulation of ornithine decarboxylase is not essential for mesangial cell proliferation and matrix expansion in anti-Thy-1-nephritis.Nephrol Dial Transplant. 2000; 15: 16-22Crossref PubMed Scopus (9) Google Scholar. Furthermore, in this model, although glomeruli generate large amounts of NO in culture we found no effect on pathology after NO inhibition using L-NMMA, L-NIL or arginase. In a different model, heterologous nephrotoxic nephritis, again we found no effect after L-NIL administration despite high glomerular NO production63.Waddington SN, Mosley K, Cattell V: Induced nitric oxide (NO) synthesis in heterologous nephrotoxic nephritis; effects of selective inhibition in neutrophil-dependent glomerulonephritis. Clin Exp Immunol (in press)Google Scholar. The true complexity of interactions between these enzymes is becoming illuminated by current research. The inherent interdependency of these enzymes illustrates the difficulty in isolating and studying a single metabolic pathway in an in vivo model; this necessitates interpretation that could be called gestalt pathology. With this approach, recent studies have emphasized the importance of arginase and the balance of arginine-associated pathways in glomerulonephritis and inflammation. This work was funded by the Wellcome Trust and the National Kidney Research Fund. I thank Ms. Kenza Kheireddine, Ms. Suzy Buckley and Mr. Matthew Edwards for manuscript preparation.
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