Advertisement

Amino Acids

, Volume 46, Issue 10, pp 2271–2286 | Cite as

l-Arginine and its metabolites in kidney and cardiovascular disease

  • Ada Popolo
  • Simona Adesso
  • Aldo Pinto
  • Giuseppina Autore
  • Stefania MarzoccoEmail author
Review Article

Abstract

l-Arginine is a semi essential amino acid synthesised from glutamine, glutamate and proline via the intestinal-renal axis in humans and most mammals. l-Arginine degradation occurs via multiple pathways initiated by arginase, nitric-oxide synthase, Arg: glycine amidinotransferase, and Arg decarboxylase. These pathways produce nitric oxide, polyamines, proline, glutamate, creatine and agmatine with each having enormous biological importance. Several disease are associated to an l-arginine impaired levels and/or to its metabolites: in particular various l-arginine metabolites may participate in pathogenesis of kidney and cardiovascular disease. l-Arginine and its metabolites may constitute both a marker of pathology progression both the rationale for manipulating l-arginine metabolism as a strategy to ameliorate these disease. A large number of studies have been performed in experimental models of kidney disease with sometimes conflicting results, which underlie the complexity of Arg metabolism and our incomplete knowledge of all the mechanisms involved. Moreover several lines of evidence demonstrate the role of l-arg metabolites in cardiovascular disease and that l-arg administration role in reversing endothelial dysfunction, which is the leading cause of cardiovascular diseases, such as hypertension and atherosclerosis. This review will discuss the implication of the mains l-arginine metabolites and l-arginine-derived guanidine compounds in kidney and cardiovascular disease considering the more recent literature in the field.

Keywords

Arginine Arginine metabolites Kidney disease Cardiovascular disease 

Notes

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. Aiello S, Noris M, Todesehini M et al (1997) Renal and systemic NO synthesis in rats with renal mass reduction. Kidney Int 52:171–181PubMedGoogle Scholar
  2. Alderton WK, Cooper CE, Knowles RG (2001) Nitric oxide synthase: structure, function and inhibition. Biochem J 357:593–615PubMedPubMedCentralGoogle Scholar
  3. Anderssohn M, Schwedhelm E, Lüneburg N, Vasan RS, Böger RH (2010) Asymmetric dimethylarginine as a mediator of vascular dysfunction and a marker of cardiovascular disease and mortality: an intriguing interaction with diabetes mellitus. Diab Vasc Dis Res 7(2):105–118PubMedGoogle Scholar
  4. Anderstam B, Katzarski K, Bergstrom J (1997) Serum levels of NG, NG-dimethyl-l-arginine, a potential endogenous nitric oxide inhibitor in dialysis patients. J Am Soc Nephrol 8:1437–1442PubMedGoogle Scholar
  5. Asaka M, Iida H, Izumino K, Sasayama S (1988) Depressed natural killer cell activity in uremia. Nephron 49:291–295PubMedGoogle Scholar
  6. Ataya B, Tzeng E, Zuckerbraun BR (2011) Nitrite-generated Nitric oxide to protect against intimal hyperplasia formation. Trends Cardiovasc 21:157–162Google Scholar
  7. Autore G, Marzocco S, Sorrentino R, Mirone VG, Baydoun A, Pinto A (1999) In vitro and in vivo TNFalpha synthesis modulation by methylguanidine, an uremic catabolyte. Life Sci 65(11):PL121–PL127PubMedGoogle Scholar
  8. Bagdade JD, Subbaiah PV, Bartos D, Bartos F, Campbell RA (1979) Polyamines: an unrecognised cardiovascularrisk factor in chronic dialysis? Lancet 1:412–413PubMedGoogle Scholar
  9. Baylis C (2006) Arginine, arginine analogs and nitric oxide production in chronic kidney disease (CKD). Nature Clinical Practice Nephrology 2:209–220PubMedPubMedCentralGoogle Scholar
  10. Baylis C (2008) Nitric oxide deficiency in chronic kidney disease. Am J Physiol Renal Physiol 294:F1–F9PubMedGoogle Scholar
  11. Bellinghieri G, Santoro D, Mallamace A, Savica V (2006) l-arginine: a new opportunity in the management of clinical derangement in dialysis patients. J Renal Nutr 16:245–247Google Scholar
  12. Beltowski J, Kedra A (2006) Asymmetric dimethyl arginine (ADMA) as a target for pharmacotherapy. Pharmacol Rep 58:159–178PubMedGoogle Scholar
  13. Betz B, Möller-Ehrlich K, Kress T, Kniepert J, Schwedhelm E, Böger RH, Wanner C, Sauvant C, Schneider R (2013) Increased symmetrical dimethylarginine in ischemic acute kidney injury as a causative factor of renal l-arginine deficiency. Transl Res 162(2):67–76PubMedGoogle Scholar
  14. Blantz RC, Satriano J, Gabbai F, Kelly C (2000) Biological effects of arginine metabolites. Acta Physiol Scand 168(1):21–25PubMedGoogle Scholar
  15. Bodamer OA, Sahoo T, Beaudet AL, O’Brien WE, Bottiglieri T, Stockler-Ipsiroglu S, Wagner C, Scaglia F (2005) Creatine metabolism in combined methylmalonic aciduria and homocystinuria. Ann. Neurol 57:557–560PubMedGoogle Scholar
  16. Böger RH, Ron ES (2005) l-arginine improves vascular function by overcoming deleterious effects of ADMA, a novel cardiovascular risk factor. Altern Med Rev 10(1):14–23PubMedGoogle Scholar
  17. Böger RH, Maas R, Schulze F, Schwedhelm E (2009) Asymmetric dimethylarginine (ADMA) as a prospective marker of cardiovascular disease and mortality-an update on patient populations with a wide range of cardiovascular risk. Pharmacol Res 60:481–487PubMedGoogle Scholar
  18. Boudy N, Hassler C, Parvy P, Bankir L (1993) Renal synthesis of arginine in CRF; In vivo and in vitro studies in rats with 5/6 nephrectomy. Kidney Int 44:676–683Google Scholar
  19. Caglar K, Yilmaz MI, Sonmez A, Cakir E, Kaya A, Acikel C, Eyileten T, Yenicesu M, Oguz Y, Bilgi C et al (2006) ADMA, proteinuria, and insulin resistance in non-diabetic stage I chronic kidney disease. Kidney Int 70:781–787PubMedGoogle Scholar
  20. Caldarera CM, Casti A, Rossoni C, Visioli O (1971) Polyamines and noradrenaline following myocardial hypertrophy. J Mol Cell Cardiol 3(1):121–126PubMedGoogle Scholar
  21. Caldarera CM, Casti A, Guarnier C, Moruzzi G (1975) Regulation of ribonucleic acid synthesis by polyamines. Reversal by spermine of inhibition by methylglyoxal bis(guanylhydrazone) of ribonucleic acid synthesis and histone acetylation in rabbit heart. Biochem J 152(1):91–98PubMedPubMedCentralGoogle Scholar
  22. Campbell RA (1987) Polyamines and uremia. Adv Exp Med Biol 223:47–54PubMedGoogle Scholar
  23. Carlström M, Persson AE, Larsson E et al (2011) Dietary nitrate attenuates oxidative stress, prevents cardiac and renal injuries, and reduces blood pressure in salt-induced hypertension. Cardiovasc Res 89:574–585PubMedGoogle Scholar
  24. Castillo L, Sanchez M, Vogt J, Chapman TE, DeRojas-Walker TC, Tannenbaum SR, Ajami AM, Young VR (1995) Plasma arginine, citrulline, and ornithine kinetics in adults, with observations on nitric oxide synthesis. Am J Physiol 268:E360–E367PubMedGoogle Scholar
  25. Chan W, Wang M, Kopple J, Swenseid M (1974) Citrulline levels and urea cycle enzymes in uremic rats. J Nutr 104:678–683PubMedGoogle Scholar
  26. Chatterjee PK, Patel NS, Kvale EO, Cuzzocrea S, Brown PA, Stewart KN, Mota-Filipe H, Thiemermann C (2002) Inhibition of inducible nitric oxide synthase reduces renal ischemia/reperfusion injury. Kidney Int 61:862–871PubMedGoogle Scholar
  27. Cherla G, Jaimes EA (2004) Role of l-arginine in the pathogenesis and treatment of renal disease arginine metabolism: enzymology, nutrition, and clinical significance. J Nutr 134:2801S–2806SPubMedGoogle Scholar
  28. Clarkson P, Adams MR, Powe AJ et al (1996) Oral l-arginine improves endothelium-dependent dilation in hypercholesterolemic young adults. J Clin Invest 97:1989–1994PubMedPubMedCentralGoogle Scholar
  29. Conference D (1987) Oxygen radicals and human disease. Ann Int Med 107:526–545Google Scholar
  30. Conger JD, Robinette JB, Schrier RW (1988) Smooth muscle calcium and endothelium-derived relaxing factor in the abnormal vascular responses of acute renal failure. J Clin Invest 82:532–537PubMedPubMedCentralGoogle Scholar
  31. Conger J, Robinette J, Villar A, Raij L, Shultz P (1995) Increased nitric oxide synthase activity despite lack of response to endothelium dependent vasodilators in postischemic acute renal failure in rats. J Clin Invest 96:631–638PubMedPubMedCentralGoogle Scholar
  32. Cubría JC, Reguera R, Balaña-Fouce R, Ordóñez C, Ordóñez D (1998) Polyamine-mediated heart hypertrophy induced by clenbuterol in the mouse. J Pharm Pharmacol 50(1):91–96PubMedGoogle Scholar
  33. D’Hooge R, Pei YQ, Marescau B, De Deyn PP (1992) Convulsive action and toxicity of uremic guanidino compounds: behavioral assessment and relation to brain concentration in adult mice. J Neurol Sci 112:96–105PubMedGoogle Scholar
  34. D’Hooge R, De Deyn PP, Van De Vijver G et al (1999) Uraemic guanidine compounds inhibit gamma-aminobutyric acid-evoked whole cell currents in mouse spinal cord neurones. Neurosci Lett 265:83–86PubMedGoogle Scholar
  35. Davis TA, Nguyen HV, Garciaa-Bravo R et al (1994) Amino acid composition of human milk is not unique. J Nutr 124:1126–1132PubMedGoogle Scholar
  36. De Deyn PP, MacDonald RL (1990) Guanidino compounds that are increased in uremia inhibit GABA and glycine responses on mouse neurons in cell culture. Ann Neurol 28:627–633PubMedGoogle Scholar
  37. De Deyn P, Marescau B, Lornoy W et al (1986) Guanidino compounds in uraemic dialysed patients. Clin Chim Acta 157:143–150PubMedGoogle Scholar
  38. De Deyn P, Marescau B, Lornoy W et al (1987) Serum guanidino compound levels and the influence of a single hemodialysis in uremic patients undergoing maintenance hemodialysis. Nephron 45:291–295PubMedGoogle Scholar
  39. De Deyn PP, Vanholder R, D’Hooge R (2003) Nitric oxide in uremia: effects of several potentially toxic guanidino compounds. Kidney Int Suppl 84:S25–S28PubMedGoogle Scholar
  40. Durante W, Johnson FK, Johnson RA (2007) Arginase: a critical regulator of nitric oxide synthesis and vascular function. ClinExp Pharmacol 34:906–911Google Scholar
  41. El-Mesallamy HO, Abdel Hamid SG, Gad MZ (2008) Oxidative stress and asymmetric dimethylarginine are associated with cardiovascular complications in hemodialysis patients: improvements by l-arginine intake. Kidney Blood Press Res 31:189–195PubMedGoogle Scholar
  42. Eloot S, Schepers E, Barreto DV, Barreto FC, Liabeuf S, Van Biesen W et al (2011) Estimated glomerular filtration rate is a poor predictor of concentration for a broad range of uremic toxins. Clin J Am Soc Nephrol 6:1266–1273PubMedPubMedCentralGoogle Scholar
  43. Forslund T, Nilsson HM, Sundqvist T (2000) Nitric oxide regulates the aggregation of stimulated human neutrophils. Biochem Biophys Res Commun 274(2):482–487PubMedGoogle Scholar
  44. Fujii H, Kono K, Nakai K, Goto S, Kitazawa R, Fukagawa M, Nishi S (2014) Renin-angiotensin system inhibitors reduce serum asymmetric dimethylarginine levels and oxidative stress in normotensive patients with chronic kidney disease. Nephron Extra 4:18–25PubMedPubMedCentralGoogle Scholar
  45. Fukunaga Y, Itoh H, Doi K, Tanaka T, Yamashita J, Chun TH, Inoue M, Masatsugu K, Sawada N, Saito T, Hosoda K, Kook H, Ueda M, Nakao K (2001) Thiazolidinediones, peroxisome proliferator-activated receptor gamma agonists, regulate endothelial cell growth and secretion of vasoactive peptides. Atherosclerosis 158(1):113–119PubMedGoogle Scholar
  46. Gilchrist M, Shore AC, Benjamin N (2011) Inorganic nitrate and nitrite and control of blood pressure. Cardiovasc Res 89:492–498PubMedGoogle Scholar
  47. Giovannetti S, Cioni L, Balestri PL, Biagnini M (1968) Evidence that guanidines and some related compounds cause haemolysis in chronic uraemia. Clin Sci 34:141–148PubMedGoogle Scholar
  48. Giovannetti S, Biagnini M, Balestri PL et al (1969) Uraemia-like sindrome in dogs chronically intoxicated with methylguanidine and creatinine. Clin Sci 36:445–452PubMedGoogle Scholar
  49. Glorieux G, Dhondt A, Jacobs P et al (2004) In vitro study of the potential role of guanidines in leukocyte functions related to atherogenesis and infection. Kidney Int 65:1–9Google Scholar
  50. Goligorsky MS, Noiri E (1999) Duality of nitric oxide in acute renal injury. Semin Nephrol 19:263–271PubMedGoogle Scholar
  51. Goligorsky MS, Brodsky SV, Noiri E (2002) Nitric oxide in acute renal failure: NOS versus NOS. Kidney Int 61(3):855–861PubMedGoogle Scholar
  52. Govoni M, Bonavita F, Shantz LM, Guarnieri C, Giordano E (2010) Overexpression of ornithine decarboxylase increases myogenic potential of H9c2 rat myoblasts. Amino Acids 38(2):541–547PubMedGoogle Scholar
  53. Greenberg S, Finkelstein A, Gurevich J, Brazowski E, Rosenfeld F, Shapira II, George J, Laniado S, Keren G (1999) The Effect of agmatine on ischemic and nonischemic isolated rat heart. J Cardiovasc Pharmacol Ther 4(3):151–158PubMedGoogle Scholar
  54. Greenberg S, George J, Wollman Y, Shapira I, Laniado S, Keren G (2001) The effect of agmatine administration on ischemic-reperfused isolated rat heart. J Cardiovasc Pharmacol Ther 6(1):37–45PubMedGoogle Scholar
  55. Grillo MA, Lanza A, Colombatto S (2008) Transport of amino acids through the placenta and their role. Amino Acids 34:517–523PubMedGoogle Scholar
  56. Hayde M, Vierhapper H, Lubec B, Popow C, Weninger M, Xi Z, Lubec G (1994) Low-dose dietary l-arginine increases plasma interleukin 1 alpha but not interleukin 1 beta in patients with diabetes mellitus. Cytokine 6(1):79–82PubMedGoogle Scholar
  57. Hiravama A, Noronha Dutra AA, Gordge MP, Neild GH, Hothersall JS (1997) Mechanism of inhibition by guanidino compounds on neutrophil superoxide production (Abstract). J Am Soc Nephrol 8:238AGoogle Scholar
  58. Horowitz HI, Cohen BD, Martinez P, Papayoanou MF (1967) Defective ADP-induced platelet factor 3 activation in uremia. Blood 30:331–340PubMedGoogle Scholar
  59. Hou ZP, Yin YL, Huang RL et al (2008) Rice protein concentrate partially replaces dried whey in the diet for early-weaned piglets and improves their growth performance. J Sci Food Agric 88:1187–1193Google Scholar
  60. Igarashi K, Kashiwagi K (2011a) Protein-conjugated acrolein as a biochemical marker of brain infarction. Mol Nutr Food Res 55:1332–1341PubMedGoogle Scholar
  61. Igarashi K, Kashiwagi K (2011b) Use of polyamine metabolites as markers for stroke and renal failure. Methods Mol Biol 720:395–408PubMedGoogle Scholar
  62. Igarashi K, Ueda S, Yoshida K, Kashiwagi K (2006) Polyamines in renal failure. Amino Acids 31:477–483PubMedGoogle Scholar
  63. Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G (1987) Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci USA 84:9265–9269PubMedPubMedCentralGoogle Scholar
  64. Ishibashi Y, Yamagishi S, Matsui T et al (2012) Pravastatin inhibits advanced glycation end products (AGEs)-induced proximal tubular cell apoptosis and injury by reducing receptor for AGEs (RAGE) level. Metabolism 61:1067–1072PubMedGoogle Scholar
  65. Ito A, Tsao PS, Adimoolam S, Kimoto M, Ogawa T, Cooke JP (1999) Novel mechanism for endothelial dysfunction: dysregulation of dimethylarginine dimethylaminohydrolase. Circulation 99(24):3092–3095PubMedGoogle Scholar
  66. Ito K, Chen J, Seshan SV et al (2005) Dietary arginine supplementation attenuates renal damage after relief of unilateralureteral obstruction in rats. Kidney Int 68:515–528PubMedGoogle Scholar
  67. Jaimes EA, del Castillo D, Rutherford MS, Raij L (2001) Countervailing influence of tumor necrosis factor-alpha and nitric oxide in endotoxemia. J Am Soc Nephrol 12:1204–1210PubMedGoogle Scholar
  68. Jenkinson CP, Grody WW, Cederbaum SD (1996) Comparative properties of arginases. Comp Biochem Physiol B Biochem Mol Biol 114:107–132PubMedGoogle Scholar
  69. Jover B, Herizi A, Ventre F, Dupont M, Mimran A (1993) Sodium and angiotensin in hypertension induced by long-term nitric oxide blockade. Hypertension 21:944–948PubMedGoogle Scholar
  70. Kaida Y, Ueda S, Yamagishi S et al (2012) Proteinuria elevates asymmetric dimethylarginine levels via protein arginine methyltransferase-1 overexpression in a rat model of nephrotic syndrome. Life Sci 91:301–305PubMedGoogle Scholar
  71. Kajimoto H, Kai H, Aoki H et al (2012) Inhibition of eNOS phosphorylation mediates endothelial dysfunction in renal failure: new effect of asymmetric dimethylarginine. Kidney Int 81:762–768PubMedGoogle Scholar
  72. Kanagy NL, Charpie JR, Webb RC (1995) Nitric oxide regulation of ADP-ribosylation of G proteins in hypertension. Med Hypotheses 44(3):159–164PubMedGoogle Scholar
  73. Kharitonov SA, Lubec G, Lubec B, Hjelm M, Barnes PJ (1995) l-arginine increases exhaled nitric oxide in normal human subjects. Clin Sci Lond 88(2):135–139PubMedGoogle Scholar
  74. Kielstein JT, Salpeter SR, Bode-Boeger SM, Cooke JP, Fliser D (2006) Symmetric dimethylarginine (SDMA) as endogenous marker of renal function–a meta-analysis. Nephrol Dial Transpl 21:2446–2451Google Scholar
  75. Kielstein JT, Fliser D, Veldink H (2009) Asymmetric dimethylarginine and symmetric dimethylarginine: axis of evil or useful alliance? Semin Dial 22:346–350PubMedGoogle Scholar
  76. King DE, Mainous AG, Geesey ME (2008) Variation in l-arginine intake follow demographics and lifestyle factors that may impact cardiovascular disease risk. Nutr Res 28:21–24PubMedPubMedCentralGoogle Scholar
  77. Kittel A, Maas R, Konig J et al (2013) In vivo evidence that Agxt2 can regulate plasma levels of dimethylarginines in mice. Biochem Biophys Res Commun 430:84–89PubMedGoogle Scholar
  78. Kone BC (1997) Nitric oxide in renal health and disease. Am J Kidney Dis 30:311–333PubMedGoogle Scholar
  79. Kopincova J, Pύzserovà A, Bernátova I (2012) L_NAME in the cardiovascular system-nitric oxide synthase activator? Pharmacol Rep 64:511–520PubMedGoogle Scholar
  80. Lakshmi SV, Padmaja G, Kuppusamy P, Kutala VK (2009) Oxidative stress in cardiovascular disease. Indian J Biochem Biophys 46(6):421–440PubMedGoogle Scholar
  81. Leiper JM, Santa Maria J, Chubb A, MacAllister RJ, Charles IG, Whitley GS, Vallance P (1999) Identification of two human dimethylarginine dimethyla- minohydrolases with distinct tissue distributions and homology with micro- bial arginine deiminases. Biochem J 343:209–214PubMedPubMedCentralGoogle Scholar
  82. Li G, Regunathan S, Barrow CJ, Eshraghi J, Cooper R, Reis DJ (1994) Agmatine: an endogenous clonidine-displacing substance in the brain. Science 263:966–969PubMedGoogle Scholar
  83. Li G, Regunathan S, Reis DJ (1995) Agmatine is synthesized by a mitochondrial arginine decarboxylase in rat brain. Ann N Y Acad Sci 763:325–329PubMedGoogle Scholar
  84. Li H, Meininger CJ, Hawker JR Jr, Haynes TE et al (2001) Regulatory role of arginase I and II in nitric oxide, polyamine, and proline syntheses in endothelial cells. Am J Physiol Endocrinol Metab 280:E75–E82PubMedGoogle Scholar
  85. Li H, Meininger CJ, Kelly KA, Hawker JR Jr, Morris SM Jr, Wu G (2002) Activities of arginase I and II are limiting for endothelial cell proliferation. Am J Physiol Regul Integr Comp Physiol 282:R64–R69PubMedGoogle Scholar
  86. Ligthart-Melis GC, van de Poll MCG, Boelens PG et al (2008) Glutamine is an important precursor for de novo synthesis of arginine in humans. Am J Clin Nutr 87:1282–1289PubMedGoogle Scholar
  87. Lin KY, Ito A, Asagami T et al (2002) Impaired nitric oxide synthase pathway in diabetes mellitus: role of asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase. Circulation 106:987–992PubMedGoogle Scholar
  88. Lin Y, Wang LN, Xi YH, Li HZ, Xiao FG, Zhao YJ, Tian Y, Yang BF, Xu CQ (2008) l-arginine inhibits isoproterenol-induced cardiac hypertrophy through nitric oxide and polyamine pathways. Basic Clin Pharmacol Toxicol 103(2):124–130PubMedGoogle Scholar
  89. Lortie MJ, Novotny WF, Peterson OW, Vallon V, Malvey K, Mendonca M, Satriano J, Insel P, Thomson SC, Blantz RC (1996) Agmatine, a bioactive metabolite of arginine. Production, degradation, and functional effects in the kidney of the rat. J Clin Invest 97:413–420PubMedPubMedCentralGoogle Scholar
  90. Lubec B, Aufricht C, Herkner K, Hoeger H, Adamiker D, Gialamas H, Fang-Kircher S, Lubec G (1994) Creatine reduces collagen accumulation in the kidneys of diabetic db/db mice. Nephron 67(2):214–217PubMedGoogle Scholar
  91. Lubec B, Golej J, Marx M, Weninger M, Hoeger H (1995) l-arginine reduces kidney lipid peroxidation, glycoxidation and collagen accumulation in the aging NMRI mouse. Ren Physiol Biochem 18(2):97–102PubMedGoogle Scholar
  92. Lubec B, Hoeger H, Kremser K, Amann G, Koller DY, Gialamas J (1996) Decreased tumor incidence and increased survival by one year oral low dose arginine supplementation in the mouse. Life Sci 58(25):2317–2325PubMedGoogle Scholar
  93. Lubec B, Aufricht C, Amann G, Kitzmüller E, Höger H (1997a) Arginine reduces kidney collagen accumulation, cross-linking, lipid peroxidation, glycoxidation, kidney weight and albuminuria in the diabetic kk mouse. Nephron 75(2):213–218PubMedGoogle Scholar
  94. Lubec B, Hayn M, Kitzmüller E, Vierhapper H, Lubec G (1997b) l-arginine reduces lipid peroxidation in patients with diabetes mellitus. Free Radic Biol Med 22(1–2):355–357PubMedGoogle Scholar
  95. Macallister RJ, Whitley GS, Vallance P (1994) Effects of guanidine and uremic compounds on nitric oxide pathways. Kidney Int 45:737–742PubMedGoogle Scholar
  96. Marescau B, Nagles G, Possemiers I et al (1997) Guanidino compounds in serum and urine of nondialyzed patients with chronic renal insufficiency. Metabolism 46:1024–1031PubMedGoogle Scholar
  97. Martens CR, Edwards DG (2011) Peripheral vascular dysfunction in chronic kidney disease. Cardiol Res Pract 2011:257–267Google Scholar
  98. Martens-Lobenhoffer J, Rodionov RN, Drust A, Bode-Böger SM (2011) Detection and quantification of a keto d-(N(G), N(G)-dimethylguanidino) valeric acid: a metabolite of a symmetric dimethylarginine. Anal Biochem 419:234–240PubMedGoogle Scholar
  99. Marx M, Trittenwein G, Aufricht C, Hoeger H, Lubec B (1995) Agmatine and spermidine reduce collagen accumulation in kidneys of diabetic db/db mice. Nephron 69:155–158PubMedGoogle Scholar
  100. Marzocco S, Di Paola R, Genovese T, Sorrentino R, Britti D, Scollo G, Pinto A, Cuzzocrea S, Autore G (2004a) Methylguanidine reduces the development of non septic shock induced by zymosan in mice. Life Sci 75(12):1417–1433PubMedGoogle Scholar
  101. Marzocco S, Di Paola R, Ribecco MT, Sorrentino R, Domenico B, Genesio M, Pinto A, Autore G, Cuzzocrea S (2004b) Effect of methylguanidine in a model of septic shock induced by LPS. Free Radic Res 38(11):1143–1153PubMedGoogle Scholar
  102. Marzocco S, Di Paola R, Serraino I, Sorrentino R, Meli R, Mattaceraso G, Cuzzocrea S, Pinto A, Autore G (2004c) Effect of methylguanidine in carrageenan-induced acute inflammation in the rats. Eur J Pharmacol 484(2–3):341–350PubMedGoogle Scholar
  103. Marzocco S, Popolo A, Bianco G, Pinto A, Autore G (2010) Pro-apoptotic effect of methylguanidine on hydrogen peroxide-treated rat glioma cell line. Neurochem Int 57(5):518–524PubMedGoogle Scholar
  104. Marzocco S, Adesso S, Autore G (2013a) Guanidino compounds inhibit nitric oxide release in J774A.1 macrophages Pharmacology. OnLine 2:60–67Google Scholar
  105. Marzocco S, Adesso S, Autore G (2013b) Time related inhibition by methylguanidine in LPS-stimulated J774A.1 macrophages. Pharmacol OnLine 2:43–49Google Scholar
  106. Matsuguma K, Ueda S, Yamagishi S, Matsumoto Y, Kaneyuki U, Shibata R, Fujimura T, Matsuoka H, Kimoto M, Kato S, Imaizumi T, Okuda S (2006) Molecular mechanism for elevation of asymmetric dimethylarginine and its role for hypertension in chronic kidney disease. J Am Soc Nephrol 17(8):2176–2183PubMedGoogle Scholar
  107. Matsumoto M, Mori A (1976) Convulsive activity of methylguanidine incat and rabbits. IRCS Med Sci 4:65Google Scholar
  108. Matsumoto A, Hirata Y, Kakoki M et al (1999) Increased excretion of Nitric oxide in exhaled air of patients with chronic renal failure. Clin Sci 96:67–74PubMedGoogle Scholar
  109. Matsumoto Y, Ueda S, Yamagishi S, Matsuguma K, Shibata R, Fukami K, Matsuoka H, Imaizumi T, Okuda S (2007) Dimethylarginine dimethylaminohydrolase prevents progression of renal dysfunction by inhibiting loss of peritubular capillaries and tubulointerstitial fibrosis in a rat model of chronic kidney disease. J Am Soc Nephrol 18:1525–1533PubMedGoogle Scholar
  110. Mihout F, Shweke N, Bigé N, Jouanneau C, Dussaule JC, Ronco P, Chatziantoniou C, Boffa JJ (2011) Asymmetric dimethylarginine (ADMA) induces chronic kidney disease through a mechanism involving collagen and TGF-β1 synthesis. J Pathol 223(1):37–45PubMedGoogle Scholar
  111. Mitch W, Chesney R (1983) Amino acid metabolism by the kidney. Miner Electrolyte Metab 9:190–202PubMedGoogle Scholar
  112. Moncada S (1997) Nitric oxide in the vasculature: physiology and pathophysiology. Ann NY Acad Sci 811:60–67 (discussion 67–69)PubMedGoogle Scholar
  113. Morris SM Jr (2007) Arginine metabolism: boundaries of our knowledge. J Nutr 137:1602S–1609SPubMedGoogle Scholar
  114. Morris DR, Davis R, Coffino P (1991) A new perspective on ornithine decarboxylase regulation: prevention of polyamine toxicity is the overriding theme. J Cell Biochem 46:102–105PubMedGoogle Scholar
  115. Morrissey JJ, Klahr S (1997) Agmatine activation of nitric oxide synthase in endothelial cells. Trans Assoc Am Physicians 109:51–57Google Scholar
  116. Morrissey J, McCracken R, Ishidoya S, Klahr S (1995) Partial cloning and characterization of an arginine decarboxylase in the kidney. Kidney Int 47:1458–1461PubMedGoogle Scholar
  117. Nakayama Y, Ueda S, Yamagishi S, Obara N, Taguchi K, Ando R, Kaida Y, Iwatani R, Kaifu K, Yokoro M, Toyonaga M, Kusumoto T, Fukami K, Okuda S (2014) Asymmetric dimethylarginine accumulates in the kidney during ischemia/reperfusion injury. Kidney Int 85(3):570–578PubMedPubMedCentralGoogle Scholar
  118. O’Quinn PR, Knabe DA, Wu G (2002) Arginine catabolism in lactating porcine mammary tissue. J Anim Sci 80:467–474PubMedGoogle Scholar
  119. Odenlund M, Holmqvist B, Baldetorp B et al (2008) Polyamine synthesis inhibition induces S phase cell cycle arrest in vascular smooth muscle cells. Amino Acids. doi: 10.1007/s00726-008-0060-7 PubMedGoogle Scholar
  120. Ogawa T, Kimoto M, Sasaoka K (1989) Purification and properties of a new enzyme, N, N-dimethylarginine dimethylaminohydrolase, from rat kidney. J Biol Chem 264:10205–10209PubMedGoogle Scholar
  121. Okubo K, Hayashi K, Wakino S, Matsuda H, Kubota E, Honda M, Tokuyama H, Yamamoto T, Kajiya F, Saruta T (2005) Role of asymmetrical dimethylarginine in renal microvascular endothelial dysfunction in chronic renal failure with hypertension. Hypertens Res 28:181–189PubMedGoogle Scholar
  122. Onozato ML, Tojo A, Leiper J, Fujita T, Palm F, Wilcox CS (2008) Expression of NG, NG-dimethylarginine dimethylaminohydrolase and protein arginine N-methyltransferase isoforms in diabetic rat kidney: effects of angiotensin II receptor blockers. Diabetes 57:172–180PubMedGoogle Scholar
  123. Orlando GF, Wolf G, Engelmann M (2008) Role of neuronal nitric oxide synthase in the regulation of the neuroendocrine stress response in rodents: insights from mutant mice. Amino Acids 35:17–27PubMedGoogle Scholar
  124. Pegg AE (2013) Toxicity of polyamines and their metabolic products. Chem Res Toxicol 26:1782–1800PubMedGoogle Scholar
  125. Pegg AE, Hibasami H (1980) Polyamine metabolism during cardiac hypertrophy. Am J Physiol 239(5):E372–E378PubMedGoogle Scholar
  126. Peters H, Border WA, Noble NA (1999) l-arginine supplementation increased mesangial cell injury and subsequent tissue fibrosis in experimental glomerulonephritis. Kidney Int 55:2264–2273PubMedGoogle Scholar
  127. Pieper GM (1997) Acute amelioration of diabetic endothelial dysfunction with a derivative of the nitric oxide synthase cofactor, tetrahydrobiopterin. J Cardiovasc Pharmacol 29:8–15PubMedGoogle Scholar
  128. Popolo A, Autore G, Pinto A, Marzocco S (2013) Oxidative stress in cardiovascular and renal disease. Free Radic Res 47(5):346–356PubMedGoogle Scholar
  129. Rackè K, Warnken M (2010) l-arginine metabolic pathway. Open Nitric Oxide J 2:9–19Google Scholar
  130. Radner W, Höger H, Lubec B, Salzer H, Lubec G (1994) L-arginine reduces kidney collagen accumulation and N-epsilon-(carboxymethyl)lysine in the aging NMRI-mouse. J Gerontol 49(2):M44–M46PubMedGoogle Scholar
  131. Raghavan SAV, Dikshit M (2004) Vascular regulation by the L-arginine metabolites, nitric oxide and agmatine. Pharmacol Res 49:397–414PubMedGoogle Scholar
  132. Raij L, Baylis C (1995) Glomerular actions of nitric oxide. Kidney Int 48:20–32PubMedGoogle Scholar
  133. Rawal N, Rajpurohit R, Lischwe MA, Williams KR, Paik WK, Kim S (1995) Structural specificity of substrate for S-adenosylmethionine: protein arginine N-methyltransferases. Biochim Biophys Acta 1248:11–18PubMedGoogle Scholar
  134. Reyes AA, Karl IE, Klahr S (1994) Role of arginine in health and in renal disease. Am J Physiol 267:F331–F346PubMedGoogle Scholar
  135. Rodionov RN, Murry DJ, Vaulman SF, Stevens JW, Lentz SR (2010) Human alanine-glyoxylate aminotransferase 2 lowers asymmetric dimethylarginine and protects from inhibition of nitric oxide production. J Biol Chem 285:5385–5391PubMedPubMedCentralGoogle Scholar
  136. Saiki R, Park H, Ishii I, Yoshida M et al (2011) Brain infarction correlates more closely with acrolein than with reactive oxygen species. Biochem Biophys Res Commun 404:1044–1049PubMedGoogle Scholar
  137. Sakata K, Kashiwagi K, Sharmin S, Ueda S, Igarashi K (2003a) Acrolein produced from polyamines as one of the uraemic toxins. Biochem Soc Trans 31:371–374PubMedGoogle Scholar
  138. Sakata K, Kashiwagi K, Sharmin S, Ueda S, Irie Y, Murotani N, Igarashi K (2003b) Increase in putrescine, amine oxidase, and acrolein in plasma of renal failure patients. Biochem Biophys Res Commun 305:143–149PubMedGoogle Scholar
  139. Sastre M, Galea E, Feinstein D, Reis DJ, Regunathan S (1998) Metabolism of agmatine in macrophages: modulation by lipopolysaccharide and inhibitory cytokines. Biochem J 330:1405–1409PubMedPubMedCentralGoogle Scholar
  140. Satriano J, Matsufuji S, Murakami Y, Lortie MJ, Schwartz D, Kelly CJ, Hayashi S, Blantz RC (1998) Agmatine suppresses proliferation by frameshift induction of antizyme and attenuation of cellular polyamine levels. J Biol Chem 273:15313–15316PubMedGoogle Scholar
  141. Schepers E, Speer T, Bode-Böger SM, Fliser D, Kielstein JT (2014) Dimethylarginines ADMA and SDMA: the real water-soluble small toxins? Semin Nephrol 34:97–105PubMedGoogle Scholar
  142. Schlüter KD, Frischkopf K, Flesch M, Rosenkranz S, Taimor G, Piper HM (2000) Central role for ornithine decarboxylase in beta-adrenoceptor mediated hypertrophy. Cardiovasc Res 45(2):410–417PubMedGoogle Scholar
  143. Schneider R, Raff U, Vornberger N, Schmidt M, Freund R, Reber M, Schramm L, Gambaryan S, Wanner C, Schmidt HH, Galle J (2003) L-arginine counteracts nitric oxide deficiency and improves the recovery phase of ischemic acute renal failure in rats. Kidney Int 64:216–225PubMedGoogle Scholar
  144. Schophuizen CM, Wilmer MJ, Jansen J, Gustavsson L, Hilgendorf C, Hoenderop JG, van den Heuvel LP, Masereeuw R (2013) Cationic uremic toxins affect human renal proximal tubule cell functioning through interaction with the organic cation transporter. Pflugers Arch 465(12):1701–1714PubMedGoogle Scholar
  145. Schramm L, Heidbreder E, Lopau K, Schaar J, Zimmermann J, Harlos J, Teschner M, Ling H, Heidland A (1996) Influence of nitric oxide on renal function in toxic acute renal failure in the rat. Miner Electrolyte Metab 22:168–177PubMedGoogle Scholar
  146. Schramm L, La M, Heidbreder E, Hecker M, Beckman JS, Lopau K, Zimmermann J, Rendl J, Reiners C, Winderl S et al (2002) L-arginine deficiency and supplementation in experimental acute renal failure and in human kidney transplantation. Kidney Int 61:1423–1432PubMedGoogle Scholar
  147. Schrier RW, Wang W, Poole B, Mitra A (2004) Acute renal failure: definitions, diagnosis, pathogenesis, and therapy. J Clin Invest 114(1):5–14PubMedPubMedCentralGoogle Scholar
  148. Schwartz D, Peterson OW, Mendonca M, Satriano J, Lortie M, Blantz RC (1997) Agmatine affects glomerular filtration via a nitric oxide synthase-dependent mechanism. Am J Physiol 272:F597–F601PubMedGoogle Scholar
  149. Schwedhelm E, Maas R, Freese R, Jung D, Lukacs Z, Jambrecina A, Spickler W, Schulze F, Böger RH (2008) Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: Impact on nitric oxide metabolism. Br J Clin Pharmacol 65:51–59PubMedPubMedCentralGoogle Scholar
  150. Sharmin S, Sakata K, Kashiwagi K, Ueda S, Iwasaki S, Shirahata A, Igarashi K (2001) Polyamine cytotoxicity in the presence of bovine serum amine oxidase. Biochem Biophys Res Commun 282:228–235PubMedGoogle Scholar
  151. Shultz PJ, Raij L (1992) Endogenously synthesized nitric oxide prevents endotoxin-induced glomerular thrombosis. J Clin Invest 90:1718–1725PubMedPubMedCentralGoogle Scholar
  152. Sibal L, Agarwal SC, Home PD, Boger RH (2010) The role of asymmetric dimethylarginine (ADMA) in endothelial dysfunction and cardiovascular disease. Curr Cardiol Rev 6(2):82–90PubMedPubMedCentralGoogle Scholar
  153. Sternbergh WC, Makhoul RG, Adelman B (1993) Nitric oxidemediated, endothelium-dependent vasodilation is selectively attenuated in the postischemic extremity. Surgery 114:960–967PubMedGoogle Scholar
  154. Stratta P, Canvese C, Dogliani M et al (1991) The role of free radicals in the progression of renal disease. Am J Kid Dis 17:33–37PubMedGoogle Scholar
  155. Stühlinger MC, Tsao PS, Her JH, Kimoto M, Balint RF, Cooke JP (2001) Homocysteine impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine. Circulation 104(21):2569–2575PubMedGoogle Scholar
  156. Surks HK, Mochizuki N, Kasai Y, Georgescu SP, Tang KM, Ito M, Lincoln TM, Mendelsohn ME (1999) Regulation of myosin phosphatase by a specific interaction with cGMP- dependent protein kinase Ialpha. Science 286(5444):1583–1587PubMedGoogle Scholar
  157. Tabor CW, Rosenthal SM (1956) Pharmacology of spermine and spermidine; some effects on animals and bacteria. J Pharmacol Exp Ther 116:139–155PubMedGoogle Scholar
  158. Tabor CW, Tabor H (1984) Polyamines. Annu Rev Biochem 53:749–790PubMedGoogle Scholar
  159. Tabor CW, Tabor H (1985) Polyamines in microorganisms. Microbiol Rev 49:81–99PubMedPubMedCentralGoogle Scholar
  160. Teerlink T, Luo Z, Palm F, Wilcox CS (2009) Cellular ADMA: regulation and action. Pharmacol Res 60:448–460PubMedPubMedCentralGoogle Scholar
  161. Tipnis UR, He GY, Li S, Campbell G, Boor PJ (2000) Attenuation of isoproterenol-mediated myocardial injury in rat by an inhibitor of polyamine synthesis. Cardiovasc Pathol 5:273–280Google Scholar
  162. Tomitori H, Usui T, Saeki N, Ueda S, Kase H, Nishimura K, Kashiwagi K, Igarashi K (2005) Polyamine oxidase and acrolein as novel biochemical markers for diagnosis of cerebral stroke. Stroke 36:2609–2613PubMedGoogle Scholar
  163. Tran CT, Fox MF, Vallance P, Leiper JM (2000) Chromosomal localization, gene structure, and expression pattern of DDAH1: comparison with DDAH2 and implications for evolutionary origins. Genomics 68:101–105PubMedGoogle Scholar
  164. Tsuchiya K, Tomita S, Ishizawa K et al (2010) Dietary nitrite ameliorates renal injury in L-NAME induced hypertensive rats. Nitric Oxide 22:98–103PubMedGoogle Scholar
  165. Vallance P, Leone A, Calver A, Collier J, Moncada S (1992) Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet 339:572–575PubMedGoogle Scholar
  166. van de Poll MCG, Siroen MPC, van Leeuwen PAM et al (2007) Interorgan amino acid exchange in humans: consequences for arginine and citrulline metabolism. Am J Clin Nutr 85:167–172PubMedGoogle Scholar
  167. Vanholder R, De Smet R (1999) Pathophysiologic effects of uremic retention solutes. J Am Soc Nephrol 10:1815–1823PubMedGoogle Scholar
  168. Víteček J, Lojek A, Valacchi G, Kubala L (2012) Arginine-based inhibitors of nitric oxide synthase: therapeutic potential and challenges. Mediat Inflamm 2012:318087Google Scholar
  169. Vos IH, Rabelink TJ, Dorland B, Loos R, van Middelaar B, Grone HJ, Joles JA (2001) l-Arginine supplementation improves function and reduces inflamation in renal allografts. J Am Soc Nephrol 12:361–367PubMedGoogle Scholar
  170. Wang D, Gill PS, Chabrashvili T, Onozato ML, Raggio J, Mendonca M, Dennehy K, Li M, Modlinger P, Leiper J, Vallance P, Adler O, Leone A, Tojo A, Welch WJ, Wilcox CS (2007) Isoform-specific regulation by N(G), N(G)-dimethylarginine dimethylaminohydrolase of rat serum asym- metric dimethylarginine and vascular endothelium-derived relaxing factor/NO. Circ Res 101:627–635PubMedGoogle Scholar
  171. Watanabe S, Kusama-Eguchi K, Kobayashi H, Igarashi K (1991) Estimation of polyamine binding to macromolecules and ATP in bovine lymphocytes and rat liver. J Biol Chem 266:20803–20809PubMedGoogle Scholar
  172. Weisensee D, Lo¨w-Friedrich I, Riehle M, Bereiter-Hahn J, Schoeppe W (1993) In vitro approach to uremic cardiomyopathy. Nephron 65:392–400PubMedGoogle Scholar
  173. Wilcox CS (2012) Asymmetric dimethylarginine and reactive oxygen species: unwelcome twin visitors to the cardiovascular and kidney disease tables. Hypertension 59:375–381PubMedPubMedCentralGoogle Scholar
  174. William N (1998) NO news is good news but only for three Americans. Science 282:610–611Google Scholar
  175. Wu G (1997) Synthesis of citrulline and arginine from proline in enterocytes of postnatal pigs. Am J Physiol Gastrointest Liver Physiol 272:G1382–G1390Google Scholar
  176. Wu G, Knabe DA (1994) Free and protein-bound amino acids in sow’s colostrum and milk. J Nutr 124:2437–2444PubMedGoogle Scholar
  177. Wu G, Knabe DA (1995) Arginine synthesis in enterocytes of neonatal pigs. Am J Physiol Regul Integr Comp Physiol 269:R621–R629Google Scholar
  178. Wu G, Meininger CJ (2000) Arginine nutrition and cardiovascular function. J Nutr 130:2626–2629PubMedGoogle Scholar
  179. Wu G, Meininger CJ (2009) Nitric oxide and vascular insulin resistance. BioFactors 35(1):21–27PubMedGoogle Scholar
  180. Wu G, Morris SM Jr (1998) Arginine metabolism: nitric oxide and beyond. Biochem J 336:1–17PubMedPubMedCentralGoogle Scholar
  181. Wu G, Knabe DA, Flynn NE et al (1996) Arginine degradation in developing porcine enterocytes. Am J Physiol Gastrointest Liver Physiol 271:G913–G919Google Scholar
  182. Wu G, Bazer FW, Cudd TA et al (2007a) Pharmacokinetics and safety of arginine supplementation in animals. J Nutr 137:1673S–1680SPubMedGoogle Scholar
  183. Wu G, Bazer FW, Davis TA et al (2007b) Important roles for the arginine family of amino acids in swine nutrition and production. Livest Sci 112:8–22Google Scholar
  184. Wu G, Collins JK, Perkins-Veazie P et al (2007c) Dietary supplementation with watermelon pomace juice enhances arginine availability and ameliorates the metabolic syndrome in Zucker diabetic fatty rats. J Nutr 137:2680–2685PubMedGoogle Scholar
  185. Wu G, Bazer FW, Davis TA, Kim SW, Li P, Marc Rhoads J, Carey Satterfield M, Smith SB, Spencer TE, Yin Y (2009) Arginine metabolism and nutrition in growth, health and disease. Amino Acids 37(1):153–168PubMedPubMedCentralGoogle Scholar
  186. Yilmaz MI, Saglam M, Sonmez A et al (2007) Improving proteinuria, endothelial functions and asymmetric dimethylarginine levels in chronic kidney disease: ramipril vs. valsartan. Blood Purif 25:327–335PubMedGoogle Scholar
  187. Yokozawa T, Fujitsuka N, Oura H, Akao T, Kobashi K, Ienaga K, Nakamura K, Hattori M (1993) Purification of methylguanidine synthase from the rat kidney. Nephron 63:452–457PubMedGoogle Scholar
  188. Yoshida M, Higashi K, Kobayashi E et al (2010) Correlation between images of silent brain infarction, carotid atherosclerosis and white matter hyperintensity, and plasma levels of acrolein, IL-6 and CRP. Atherosclerosis 211:475–479PubMedGoogle Scholar
  189. Zahedi K, Bissler JJ, Wang Z, Josyula A, Lu L, Diegelman P, Kisiel N, Porter CW, Soleimani M (2007) Spermidine/spermine N1-acetyltransferase overexpression in kidney epithelial cells disrupts polyamine homeostasis, leads to DNA damage, and causes G2 arrest. Am J Physiol Cell Physiol 292:C1204–C1215PubMedGoogle Scholar
  190. Zahedi K, Lentsch AB, Okaya T, Barone SL, Sakai N, Witte DP, Arend LJ, Alhonen L, Jell J, Janne J, Porter CW, Soleimani M (2009) Spermidine/spermine-N1-acetyltransferase ablation protects against liver and kidney ischemia reperfusion injury in mice. Am J Physiol Gastrointest Liver Physiol 296:G899–G909PubMedPubMedCentralGoogle Scholar
  191. Zahedi K, Barone S, Kramer DL, Amlal H, Alhonen L, Janne J, Porter CW, Soleimani M (2010) The role of spermidine/spermine N1-acetyltransferase in endotoxin-induced acute kidney injury. Am J Physiol Cell Physiol 299:C164–C174PubMedPubMedCentralGoogle Scholar
  192. Zatz R, Baylis C (1998) Chronic nitric oxide inhibition model six years on. Hypertension 32:958–964PubMedPubMedCentralGoogle Scholar
  193. Zhou X, Frohlich ED (2007) Analogy of cardiac and renal complications in essential hypertension and aged SHR or L-NAME/SHR. Med Chem 3:61–65PubMedGoogle Scholar

Copyright information

© Springer-Verlag Wien 2014

Authors and Affiliations

  • Ada Popolo
    • 1
  • Simona Adesso
    • 1
  • Aldo Pinto
    • 1
  • Giuseppina Autore
    • 1
  • Stefania Marzocco
    • 1
    Email author
  1. 1.Department of PharmacyUniversity of SalernoFiscianoItaly

Personalised recommendations