Skip to main content

Advertisement

SpringerLink
Log in

Asymmetric dimethylarginine (ADMA) is a novel emerging risk factor for cardiovascular disease and the development of renal injury in chronic kidney disease

  • REVIEW ARTICLE
  • Published:
Clinical and Experimental Nephrology Aims and scope Submit manuscript

Abstract

Endothelial dysfunction due to the reduced bioavailability of nitric oxide (NO) is involved in the course of atherosclerotic cardiovascular disease as well as chronic kidney disease (CKD). NO is synthesized from L-arginine via the action of NO synthase, which is blocked by endogenous L-arginine analogues such as asymmetric dimethylarginine (ADMA). ADMA is a naturally occurring amino acid found in plasma and various types of tissues. The plasma level of ADMA is reported to be associated with cardiovascular risk factors such as hypertension, diabetes, hyperlipidemia, and CKD, and is a strong predictor for cardiovascular disease and the progression of CKD. In this review, we discuss the biology of ADMA, the molecular mechanisms of the elevation of ADMA levels in CKD, and the pathological role of ADMA in patients with CKD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. PS Parfrey RN Foley (1999) ArticleTitleThe clinical epidemiology of cardiac disease in chronic renal failure J Am Soc Nephrol 10 1606–15 Occurrence Handle1:STN:280:DyaK1Mzjt1Whuw%3D%3D Occurrence Handle10405218

    CAS  PubMed  Google Scholar 

  2. K Amann C Wanner E Ritz (2006) ArticleTitleCross-talk between the kidney and the cardiovascular system J Am Soc Nephrol 17 2112–9 Occurrence Handle1:CAS:528:DC%2BD28XosFaltr4%3D Occurrence Handle10.1681/ASN.2006030204 Occurrence Handle16825329

    Article  CAS  PubMed  Google Scholar 

  3. RF Furchgott JV Zawadzki (1980) ArticleTitleThe obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine Nature 288 373–6 Occurrence Handle1:CAS:528:DyaL3MXhtFCktbY%3D Occurrence Handle10.1038/288373a0 Occurrence Handle6253831

    Article  CAS  PubMed  Google Scholar 

  4. JP Cooke VJ Dzau (1997) ArticleTitleDerangements of the nitric oxide synthase pathway, L-arginine, and cardiovascular disease Circulation 96 379–82 Occurrence Handle1:STN:280:DyaK2szos1entA%3D%3D Occurrence Handle9244195

    CAS  PubMed  Google Scholar 

  5. JP Cooke (2000) ArticleTitleDoes ADMA cause endothelial dysfunction? Arterioscler Thromb Vasc Biol 20 2032–7 Occurrence Handle1:CAS:528:DC%2BD3cXntV2it78%3D Occurrence Handle10.1161/01.ATV.20.9.2032 Occurrence Handle10978245

    Article  CAS  PubMed  Google Scholar 

  6. DG Harrison (1997) ArticleTitleCellular and molecular mechanisms of endothelial cell dysfunction J Clin Invest 100 2153–7 Occurrence Handle1:CAS:528:DyaK2sXnt1Ggs74%3D Occurrence Handle10.1172/JCI119751 Occurrence Handle9410891 Occurrence Handle508409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. S Ueda S Yamagishi U Kaneyuki S Okuda (2006) ArticleTitleAsymmetric dimethylarginine (ADMA) and cardiovascular disease Vascular Disease Prevention 3 291–5 Occurrence Handle1:CAS:528:DC%2BD28XhtFyksb7I Occurrence Handle10.2174/1567270000603010041

    Article  CAS  Google Scholar 

  8. RH Boger SM Bode-Boger A Szuba PS Tsao JR Chan O Tangphao et al. (1998) ArticleTitleAsymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction: its role in hypercholesterolemia Circulation 98 1842–7 Occurrence Handle1:CAS:528:DyaK1cXnsVWju7o%3D Occurrence Handle10.1161/01.CIR.98.18.1842 Occurrence Handle9799202

    Article  CAS  PubMed  Google Scholar 

  9. H Miyazaki H Matsuoka JP Cooke M Usui S Ueda S Okuda et al. (1999) ArticleTitleEndogenous nitric oxide synthase inhibitor: a novel marker of atherosclerosis Circulation 99 1141–6 Occurrence Handle1:CAS:528:DyaK1MXitVels7c%3D Occurrence Handle10.1161/01.CIR.99.9.1141 Occurrence Handle10069780

    Article  CAS  PubMed  Google Scholar 

  10. M Usui H Matsuoka H Miyazaki S Ueda S Okuda T Imaizumi (1998) ArticleTitleIncreased endogenous nitric oxide synthase inhibitor in patients with congestive heart failure Life Sci 62 2425–30 Occurrence Handle1:CAS:528:DyaK1cXjsFShu7o%3D Occurrence Handle10.1016/S0024-3205(98)00225-2 Occurrence Handle9651109

    Article  CAS  PubMed  Google Scholar 

  11. VP Valkonen H Paiva JT Salonen TA Lakka T Lehtimaki J Laakso et al. (2001) ArticleTitleRisk of acute coronary event and serum concentration of asymmetrical dimethylarginine Lancet 358 2127–8 Occurrence Handle1:CAS:528:DC%2BD38XitV2gtg%3D%3D Occurrence Handle10.1016/S0140-6736(01)07184-7 Occurrence Handle11784629

    Article  CAS  PubMed  Google Scholar 

  12. L Tarnow P Hovind T Teerlink CD Stehouwer HH Parving (2004) ArticleTitleElevated plasma asymmetric dimethylarginine as a marker of cardiovascular morbidity in early diabetic nephropathy in type 1 diabetes Diabetes Care 27 765–9 Occurrence Handle1:CAS:528:DC%2BD2cXisFKnsL8%3D Occurrence Handle10.2337/diacare.27.3.765 Occurrence Handle14988299

    Article  CAS  PubMed  Google Scholar 

  13. C Zoccali S Bode-Boger F Mallamaci F Benedetto G Tripepi L Malatino et al. (2001) ArticleTitlePlasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study Lancet 358 2113–7 Occurrence Handle1:CAS:528:DC%2BD38XitV2gsQ%3D%3D Occurrence Handle10.1016/S0140-6736(01)07217-8 Occurrence Handle11784625

    Article  CAS  PubMed  Google Scholar 

  14. V Achan M Broadhead M Malaki G Whitley J Leiper R MacAllister et al. (2003) ArticleTitleAsymmetric dimethylarginine causes hypertension and cardiac dysfunction in humans and is actively metabolized by dimethylarginine dimethylaminohydrolase Arterioscler Thromb Vasc Biol 23 1455–9 Occurrence Handle1:CAS:528:DC%2BD3sXlvFaqsL8%3D Occurrence Handle10.1161/01.ATV.0000081742.92006.59 Occurrence Handle12805079

    Article  CAS  PubMed  Google Scholar 

  15. SA Fickling DP Holden JE Cartwright SS Nussey P Vallance GS Whitley (1999) ArticleTitleRegulation of macrophage nitric oxide synthesis by endothelial cells: a role for NG,NG-dimethylarginine Acta Physiol Scand 167 145–50 Occurrence Handle1:CAS:528:DyaK1MXntVSrurs%3D Occurrence Handle10.1046/j.1365-201x.1999.00587.x Occurrence Handle10571550

    Article  CAS  PubMed  Google Scholar 

  16. RH Böger K Sydow J Borlak T Thum H Lenzen B Schubert et al. (2000) ArticleTitleLDL cholesterol upregulates synthesis of asymmetrical dimethylarginine in human endothelial cells: involvement of S-adenosylmethionine-dependent methyltransferases Circ Res 87 99–105 Occurrence Handle10.1161/01.RES.87.2.99 Occurrence Handle10903992

    Article  PubMed  Google Scholar 

  17. S Anthony J Leiper P Vallance (2005) ArticleTitleEndogenous production of nitric oxide synthase inhibitors Vasc Med 10 S3–9 Occurrence Handle10.1177/1358836X0501000102 Occurrence Handle16444863

    Article  PubMed  Google Scholar 

  18. J Lee J Sayegh J Daniel S Clarke MT Bedford (2005) ArticleTitlePRMT8, a new membrane-bound tissue-specific member of the protein arginine methyltransferase family J Biol Chem 280 3290–6

    Google Scholar 

  19. JR Cook JH Lee ZH Yang CD Krause N Herth R Hoffmann et al. (2006) ArticleTitleFBXO11/PRMT9, a new protein arginine methyltransferase, symmetrically dimethylates arginine residues Biochem Biophys Res Commun 342 472–81 Occurrence Handle1:CAS:528:DC%2BD28XhvVehsrY%3D Occurrence Handle10.1016/j.bbrc.2006.01.167 Occurrence Handle16487488

    Article  CAS  PubMed  Google Scholar 

  20. N Rawal R Rajpurohit WK Paik S Kim (1994) ArticleTitlePurification and characterization of S-adenosylmethionine-protein-arginine N-methyltransferase from rat liver Biochem J 300 483–9 Occurrence Handle1:CAS:528:DyaK2cXksFarsb8%3D Occurrence Handle10.1042/bj3000483 Occurrence Handle8002954 Occurrence Handle1138188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. SK Ghosh WK Paik S Kim (1988) ArticleTitlePurification and molecular identification of two protein methylase I from calf brain: myelin basic protein- and histone-specific enzyme J Biol Chem 263 19 024–33

    Google Scholar 

  22. JD Gary S Clarke (1998) ArticleTitleRNA and protein interactions modulated by protein arginine methylation Prog Nucleic Acid Res Mol Biol 61 65–131 Occurrence Handle1:CAS:528:DyaK1MXhsVWm Occurrence Handle10.1016/S0079-6603(08)60825-9 Occurrence Handle9752719

    Article  CAS  PubMed  Google Scholar 

  23. T Osanai M Saitoh S Sasaki H Tomita T Matsunaga K Okumura (2003) ArticleTitleEffect of shear stress on asymmetric dimethylarginine release from vascular endothelial cells Hypertension 42 985–90 Occurrence Handle1:CAS:528:DC%2BD3sXosFClsrw%3D Occurrence Handle10.1161/01.HYP.0000097805.05108.16 Occurrence Handle14557285

    Article  CAS  PubMed  Google Scholar 

  24. T Ogawa M Kimoto K Sasaoka (1987) ArticleTitleOccurrence of a new enzyme catalyzing the direct conversion of NG, NG-dimethyl-L-arginine to L-citrulline in rats Biochem Biophys Res Commun 148 671–7 Occurrence Handle1:CAS:528:DyaL1cXltFOnsg%3D%3D Occurrence Handle10.1016/0006-291X(87)90929-6 Occurrence Handle3689365

    Article  CAS  PubMed  Google Scholar 

  25. KY Lin A Ito T Asagami PS Tsao S Adimoolam M Kimoto et al. (2002) ArticleTitleImpaired nitric oxide synthase pathway in diabetes mellitus: role of asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase Circulation 106 987–92 Occurrence Handle1:CAS:528:DC%2BD38XntlSqs70%3D Occurrence Handle10.1161/01.CIR.0000027109.14149.67 Occurrence Handle12186805

    Article  CAS  PubMed  Google Scholar 

  26. RJ MacAllister SA Fickling GS Whitley P Vallance (1994) ArticleTitleMetabolism of methylarginines by human vasculature; implications for the regulation of nitric oxide synthesis Br J Pharmacol 112 43–8 Occurrence Handle1:CAS:528:DyaK2cXivFCrtLk%3D Occurrence Handle10.1111/j.1476-5381.1994.tb13026.x Occurrence Handle7518309 Occurrence Handle1910311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. M Kimoto GS Whitley H Tsuji T Ogawa (1995) ArticleTitleDetection of NG,NG-dimethylarginine dimethylaminohydrolase in human tissues using a monoclonal antibody J Biochem Tokyo 117 237–8 Occurrence Handle1:CAS:528:DyaK2MXkslKksb4%3D Occurrence Handle10.1093/jb/117.2.237 Occurrence Handle7608105

    Article  CAS  PubMed  Google Scholar 

  28. M Kimoto S Miyatake T Sasagawa H Yamashita M Okita T Oka et al. (1998) ArticleTitlePurification, cDNA cloning and expression of human NG,NG-dimethylarginine dimethylaminohydrolase Eur J Biochem 258 863–8 Occurrence Handle1:CAS:528:DyaK1cXnvF2jsr8%3D Occurrence Handle10.1046/j.1432-1327.1998.2580863.x Occurrence Handle9874257

    Article  CAS  PubMed  Google Scholar 

  29. JM Leiper J Santa Maria A Chubb RJ MacAllister IG Charles GS Whitley et al. (1999) ArticleTitleIdentification of two human dimethylarginine dimethylaminohydrolases with distinct tissue distributions and homology with microbial arginine deaminases Biochem J 1343 209–14 Occurrence Handle10.1042/bj3430209

    Article  Google Scholar 

  30. RJ MacAllister H Parry M Kimoto T Ogawa RJ Russell H Hodson et al. (1996) ArticleTitleRegulation of nitric oxide synthesis by dimethylarginine dimethylaminohydrolase Br J Pharmacol 119 1533–40 Occurrence Handle1:CAS:528:DyaK2sXkt1aqsg%3D%3D Occurrence Handle10.1111/j.1476-5381.1996.tb16069.x Occurrence Handle8982498 Occurrence Handle1915783

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. S Ueda S Kato H Matsuoka M Kimoto S Okuda M Morimatsu et al. (2003) ArticleTitleRegulation of cytokine-induced nitric oxide synthesis by asymmetric dimethylarginine: role of dimethylarginine dimethylaminohydrolase Circ Res 92 226–33 Occurrence Handle1:CAS:528:DC%2BD3sXot1Kitw%3D%3D Occurrence Handle10.1161/01.RES.0000052990.68216.EF Occurrence Handle12574151

    Article  CAS  PubMed  Google Scholar 

  32. P Vallance A Leone A Calver J Collier S Moncada (1992) ArticleTitleAccumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure Lancet 339 572–5 Occurrence Handle1:STN:280:DyaK387mslOisw%3D%3D Occurrence Handle10.1016/0140-6736(92)90865-Z Occurrence Handle1347093

    Article  CAS  PubMed  Google Scholar 

  33. Y Kakimoto S Akazawa (1970) ArticleTitleIsolation and identification of NG, NG-, and NG, N′G-dimethyl-arginine, N-epsilon-mono-, di-, and trimethyllysine, and glucosylgalactosyl-, and galactosyl-delta-hydroxylysine from human urine J Biol Chem 245 5751–8 Occurrence Handle1:CAS:528:DyaE3MXhslei Occurrence Handle5472370

    CAS  PubMed  Google Scholar 

  34. JR McDermott (1976) ArticleTitleStudies on the catabolism of NG-methylarginine, NG, N′G-dimethylarginine and NG, NG-dimethylarginine in the rabbit Biochem J 154 179–84 Occurrence Handle1:CAS:528:DyaE28XhtVartbc%3D Occurrence Handle10.1042/bj1540179 Occurrence Handle1275907 Occurrence Handle1172690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. JT Kielstein RH Boger SM Bode-Boger JC Frolich H Haller E Ritz et al. (2002) ArticleTitleMarked increase of asymmetric dimethylarginine in patients with incipient primary chronic renal disease J Am Soc Nephrol 13 170–6 Occurrence Handle1:CAS:528:DC%2BD38XltV2gtw%3D%3D Occurrence Handle11752034

    CAS  PubMed  Google Scholar 

  36. D Fliser JT Kielstein H Haller SM Bode-Boger (2003) ArticleTitleAsymmetric dimethylarginine: a cardiovascular risk factor in renal disease? Kidney Int 84 S37–40 Occurrence Handle1:CAS:528:DC%2BD3sXjslCku7c%3D Occurrence Handle10.1046/j.1523-1755.63.s84.11.x

    Article  CAS  Google Scholar 

  37. K Matsuguma S Ueda S Yamagishi Y Matsumoto U Kaneyuki R Shibata et al. (2006) ArticleTitleMolecular mechanism for elevation of asymmetric dimethylarginine and its role for hypertension in chronic kidney disease J Am Soc Nephrol 17 2176–83 Occurrence Handle1:CAS:528:DC%2BD28XosFaltrg%3D Occurrence Handle10.1681/ASN.2005121379 Occurrence Handle16807406

    Article  CAS  PubMed  Google Scholar 

  38. K Okubo K Hayashi S Wakino H Matsuda E Kubota M Honda et al. (2005) ArticleTitleRole of asymmetrical dimethylarginine in renal microvascular endothelial dysfunction in chronic renal failure with hypertension Hypertens Res 28 181–9 Occurrence Handle1:CAS:528:DC%2BD2MXktlOrt7k%3D Occurrence Handle10.1291/hypres.28.181 Occurrence Handle16025746

    Article  CAS  PubMed  Google Scholar 

  39. J Himmelfarb P Stenvinkel TA Ikizler RM Hakim (2002) ArticleTitleThe elephant in uremia: oxidant stress as a unifying concept of cardiovascular disease in uremia Kidney Int 62 1524–38 Occurrence Handle1:CAS:528:DC%2BD38Xos1eksb0%3D Occurrence Handle10.1046/j.1523-1755.2002.00600.x Occurrence Handle12371953

    Article  CAS  PubMed  Google Scholar 

  40. C Zoccali F Mallamaci G Tripepi (2004) ArticleTitleNovel cardiovascular risk factors in end-stage renal disease J Am Soc Nephrol 15 77–80 Occurrence Handle10.1097/01.ASN.0000093240.84097.FE

    Article  Google Scholar 

  41. QF Yin Y Xiong (2005) ArticleTitlePravastatin restores DDAH activity and endothelium-dependent relaxation of rat aorta after exposure to glycated protein J Cardiovasc Pharmacol 45 525–32 Occurrence Handle1:CAS:528:DC%2BD2MXktFyntbc%3D Occurrence Handle10.1097/01.fjc.0000159642.44523.7f Occurrence Handle15897778

    Article  CAS  PubMed  Google Scholar 

  42. MC Stuhlinger PS Tsao JH Her M Kimoto RF Balint JP Cooke (2001) ArticleTitleHomocysteine impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine Circulation 104 2569–75 Occurrence Handle1:CAS:528:DC%2BD38Xht1eqsQ%3D%3D Occurrence Handle10.1161/hc4601.098514 Occurrence Handle11714652

    Article  CAS  PubMed  Google Scholar 

  43. LJ Millatt GS Whitley D Li JM Leiper HM Siragy RM Carey et al. (2003) ArticleTitleEvidence for dysregulation of dimethylarginine dimethylaminohydrolase I in chronic hypoxia-induced pulmonary hypertension Circulation 108 1493–8 Occurrence Handle1:CAS:528:DC%2BD3sXntlarur8%3D Occurrence Handle10.1161/01.CIR.0000089087.25930.FF Occurrence Handle12952847

    Article  CAS  PubMed  Google Scholar 

  44. LG Fine C Orphanides JT Norman (1998) ArticleTitleProgressive renal disease: the chronic hypoxia hypothesis Kidney Int 65 S74–8 Occurrence Handle1:CAS:528:DyaK1cXisVKntLg%3D

    CAS  Google Scholar 

  45. M Nangaku (2006) ArticleTitleChronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure J Am Soc Nephrol 17 17–25 Occurrence Handle1:CAS:528:DC%2BD28XhtFyqtbY%3D Occurrence Handle10.1681/ASN.2005070757 Occurrence Handle16291837

    Article  CAS  PubMed  Google Scholar 

  46. C Zoccali (2006) ArticleTitleEndothelial dysfunction and the kidney: emerging risk factors for renal insufficiency and cardiovascular outcomes in essential hypertension J Am Soc Nephrol 17 S61–3 Occurrence Handle10.1681/ASN.2005121344 Occurrence Handle16565249

    Article  PubMed  Google Scholar 

  47. C Zoccali FA Benedetto R Maas F Mallamaci G Tripepi LS Malatino et al. (2002) ArticleTitleAsymmetric dimethylarginine, C-reactive protein, and carotid intima-media thickness in end-stage renal disease J Am Soc Nephrol 13 490–6 Occurrence Handle1:CAS:528:DC%2BD38XhtlWisr4%3D Occurrence Handle10.1097/01.ASN.0000032548.18973.0F Occurrence Handle11805179

    Article  CAS  PubMed  Google Scholar 

  48. C Zoccali F Mallamaci R Maas FA Benedetto G Tripepi LS Malatino et al. (2002) ArticleTitleLeft ventricular hypertrophy, cardiac remodeling and asymmetric dimethylarginine in hemodialysis patients Kidney Int 62 339–45 Occurrence Handle1:CAS:528:DC%2BD38XlsFyqu7g%3D Occurrence Handle10.1046/j.1523-1755.2002.00437.x Occurrence Handle12081596

    Article  CAS  PubMed  Google Scholar 

  49. JM Cross A Donald PJ Vallance JE Deanfield RG Woolfson RJ MacAllister (2001) ArticleTitleHemodialysis improves endothelial function in humans Nephrol Dial Transplant 16 1823–9 Occurrence Handle1:STN:280:DC%2BD3MrhtVGltQ%3D%3D Occurrence Handle10.1093/ndt/16.9.1823 Occurrence Handle11522865

    Article  CAS  PubMed  Google Scholar 

  50. CL Smith GM Birdsey S Anthony FI Arrigoni JM Leiper P Vallance (2003) ArticleTitleDimethylarginine dimethylaminohydrolase activity modulates ADMA levels, VEGF expression, and cell phenotype Biochem Biophys Res Commun 308 984–9 Occurrence Handle1:CAS:528:DC%2BD3sXmsVGku7Y%3D Occurrence Handle10.1016/S0006-291X(03)01507-9 Occurrence Handle12927816

    Article  CAS  PubMed  Google Scholar 

  51. V Kostourou SP Robinson JE Cartwright GS Whitley (2002) ArticleTitleDimethylarginine dimethylaminohydrolase I enhances tumour growth and angiogenesis Br J Cancer 87 673–80 Occurrence Handle1:CAS:528:DC%2BD38XntVKjsrc%3D Occurrence Handle10.1038/sj.bjc.6600518 Occurrence Handle12237779 Occurrence Handle2364234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. J Jacobi K Sydow G von Degenfeld Y Zhang H Dayoub B Wang et al. (2005) ArticleTitleOverexpression of dimethylarginine dimethylaminohydrolase reduces tissue asymmetric dimethylarginine levels and enhances angiogenesis Circulation 111 1431–8 Occurrence Handle1:CAS:528:DC%2BD2MXit1Onsbg%3D Occurrence Handle10.1161/01.CIR.0000158487.80483.09 Occurrence Handle15781754

    Article  CAS  PubMed  Google Scholar 

  53. T Thum D Tsikas S Stein M Schultheiss M Eigenthaler SD Anker et al. (2005) ArticleTitleSuppression of endothelial progenitor cells in human coronary artery disease by the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine J Am Coll Cardiol 46 1693–701 Occurrence Handle1:CAS:528:DC%2BD2MXhtFKmt7%2FP Occurrence Handle10.1016/j.jacc.2005.04.066 Occurrence Handle16256870

    Article  CAS  PubMed  Google Scholar 

  54. S Moncada A Higgs (1993) ArticleTitleThe L-arginine-nitric oxide pathway N Engl J Med 329 2002–12 Occurrence Handle1:CAS:528:DyaK2cXhsF2ntrw%3D Occurrence Handle10.1056/NEJM199312303292706 Occurrence Handle7504210

    Article  CAS  PubMed  Google Scholar 

  55. AF Dominiczak DF Bohr (1995) ArticleTitleNitric oxide and its putative role in hypertension Hypertension 25 1202–11 Occurrence Handle1:CAS:528:DyaK2MXmvVChu7g%3D Occurrence Handle10.1161/01.HYP.25.6.1202 Occurrence Handle7539405

    Article  CAS  PubMed  Google Scholar 

  56. JF Arnal JB Michel DG Harrison (1995) ArticleTitleNitric oxide in the pathogenesis of hypertension Curr Opin Nephrol Hypertens 4 182–8 Occurrence Handle1:STN:280:DyaK2MzitlCisg%3D%3D Occurrence Handle10.1097/00041552-199503000-00012 Occurrence Handle7600050

    Article  CAS  PubMed  Google Scholar 

  57. JN Bech CB Nielsen EB Pedersen (1996) ArticleTitleEffects of systemic NO synthesis inhibition on RPF, GFR, Una, and vasoactive hormones in healthy humans Am J Physiol 270 F845–51 Occurrence Handle1:CAS:528:DyaK28Xjt1Ogtb4%3D Occurrence Handle8928847

    CAS  PubMed  Google Scholar 

  58. LM Ruilope JL Lahera VK Rodicio JC Romero (1994) ArticleTitleParticipation of nitric oxide in the regulation of renal function: possible role in the genesis of arterial hypertension J Hypertens 12 625–31 Occurrence Handle1:CAS:528:DyaK2cXmsFWqtrs%3D Occurrence Handle7963487

    CAS  PubMed  Google Scholar 

  59. V Achan M Broadhead M Malaki G Whitley J Leiper R MacAllister et al. (2003) ArticleTitleAsymmetric dimethylarginine causes hypertension and cardiac dysfunction in humans and is actively metabolized by dimethylarginine dimethylaminohydrolase Arterioscler Thromb Vasc Biol 23 1455–9 Occurrence Handle1:CAS:528:DC%2BD3sXlvFaqsL8%3D Occurrence Handle10.1161/01.ATV.0000081742.92006.59 Occurrence Handle12805079

    Article  CAS  PubMed  Google Scholar 

  60. RJ MacAllister P Vallance (1994) ArticleTitleNitric oxide in essential and renal hypertension J Am Soc Nephrol 5 1057–65 Occurrence Handle1:STN:280:DyaK2M7ltF2qtA%3D%3D Occurrence Handle7531511

    CAS  PubMed  Google Scholar 

  61. JT Kielstein S Simmel SM Bode-Boger HJ Roth H Schmidt-Gayk H Haller et al. (2004) ArticleTitleSubpressor dose asymmetric dimethylarginine modulates renal function in humans through nitric oxide synthase inhibition Kidney Blood Press Res 27 143–7 Occurrence Handle1:CAS:528:DC%2BD2cXns1Wgsbs%3D Occurrence Handle10.1159/000078838 Occurrence Handle15192321

    Article  CAS  PubMed  Google Scholar 

  62. H Matsuoka S Itoh M Kimoto K Kohno O Tamai Y Wada et al. (1997) ArticleTitleAsymmetrical dimethylarginine, an endogenous nitric oxide synthase inhibitor, in experimental hypertension Hypertension 29 242–7 Occurrence Handle1:CAS:528:DyaK2sXhsFOnsL8%3D Occurrence Handle10.1161/01.HYP.29.1.242 Occurrence Handle9039109

    Article  CAS  PubMed  Google Scholar 

  63. H Dayoub V Achan S Adimoolam J Jacobi MC Stuehlinger BY Wang et al. (2003) ArticleTitleDimethylarginine dimethylaminohydrolase regulates nitric oxide synthesis: genetic and physiological evidence Circulation 108 3042–7 Occurrence Handle1:CAS:528:DC%2BD3sXps1SitLg%3D Occurrence Handle10.1161/01.CIR.0000101924.04515.2E Occurrence Handle14638548

    Article  CAS  PubMed  Google Scholar 

  64. A Ito PS Tsao S Adimoolam M Kimoto T Ogawa JP Cooke (1999) ArticleTitleNovel mechanism for endothelial dysfunction: dysregulation of dimethylarginine dimethylaminohydrolase Circulation 99 3092–5 Occurrence Handle1:CAS:528:DyaK1MXktlSisLc%3D Occurrence Handle10.1161/01.CIR.99.24.3092 Occurrence Handle10377069

    Article  CAS  PubMed  Google Scholar 

  65. MC Stuhlinger PS Tsao JH Her M Kimoto RF Balint JP Cooke (2001) ArticleTitleHomocysteine impairs the nitric oxide synthase pathway. Role of asymmetric dimethylarginine Circulation 104 2569–75 Occurrence Handle1:CAS:528:DC%2BD38Xht1eqsQ%3D%3D Occurrence Handle10.1161/hc4601.098514 Occurrence Handle11714652

    Article  CAS  PubMed  Google Scholar 

  66. IH Schulman MS Zhou L Raij (2005) ArticleTitleNitric oxide, angiotensin II, and reactive oxygen species in hypertension and atherogenesis Curr Hypertens Rep 7 61–7 Occurrence Handle1:CAS:528:DC%2BD2MXht1Cmu7jF Occurrence Handle10.1007/s11906-005-0056-6 Occurrence Handle15683588

    Article  CAS  PubMed  Google Scholar 

  67. R Stocker JF Keaney SuffixJr (2004) ArticleTitleRole of oxidative modifications in atherosclerosis Physiol Rev 84 1381–478 Occurrence Handle1:CAS:528:DC%2BD2cXovVyltbo%3D Occurrence Handle10.1152/physrev.00047.2003 Occurrence Handle15383655

    Article  CAS  PubMed  Google Scholar 

  68. TJ Guzik NE West E Black D McDonald C Ratnatunga R Pillai et al. (2000) ArticleTitleVascular superoxide production by NAD(P)H oxidase: association with endothelial dysfunction and clinical risk factors Circ Res 86 E85–90 Occurrence Handle1:CAS:528:DC%2BD3cXjsVKmsbw%3D Occurrence Handle10.1161/01.RES.86.9.e85 Occurrence Handle10807876

    Article  CAS  PubMed  Google Scholar 

  69. Y Taniyama KK Griendling (2003) ArticleTitleReactive oxygen species in the vasculature: molecular and cellular mechanisms Hypertension 42 1075–81 Occurrence Handle1:CAS:528:DC%2BD3sXpsVGisr8%3D Occurrence Handle10.1161/01.HYP.0000100443.09293.4F Occurrence Handle14581295

    Article  CAS  PubMed  Google Scholar 

  70. A Ito K Egashira T Narishige K Muramatsu A Takeshita (2001) ArticleTitleRenin-angiotensin system is involved in the mechanism of increased serum asymmetric dimethylarginine in essential hypertension Jpn Circ J 65 775–8 Occurrence Handle1:CAS:528:DC%2BD3MXmvF2rtr4%3D Occurrence Handle10.1253/jcj.65.775 Occurrence Handle11548874

    Article  CAS  PubMed  Google Scholar 

  71. S Aslam T Santha A Leone C Wilcox (2006) ArticleTitleEffects of amlodipine and valsartan on oxidative stress and plasma methylarginines in end-stage renal disease patients on hemodialysis Kidney Int 70 2109–15 Occurrence Handle1:CAS:528:DC%2BD28Xht1Kju7fP Occurrence Handle10.1038/sj.ki.5001983 Occurrence Handle17063175

    Article  CAS  PubMed  Google Scholar 

  72. SF Dinneen HC Gerstein (1997) ArticleTitleThe association of microalbuminuria and mortality in non-insulin-dependent diabetes mellitus. A systematic overview of the literature Arch Intern Med 157 1413–8 Occurrence Handle1:STN:280:DyaK2szmslGitw%3D%3D Occurrence Handle10.1001/archinte.1997.00440340025002 Occurrence Handle9224218

    Article  CAS  PubMed  Google Scholar 

  73. A Jager PJ Kostense HG Ruhe RJ Heine G Nijpels JM Dekker et al. (1999) ArticleTitleMicroalbuminuria and peripheral arterial disease are independent predictors of cardiovascular and all cause mortality, especially among hypertensive subjects: 5-year follow-up of the Hoorn Study Arterioscler Thromb Vasc Biol 19 617–24 Occurrence Handle1:STN:280:DyaK1M7nsVWisQ%3D%3D Occurrence Handle10.1161/01.ATV.19.3.617 Occurrence Handle10073965

    Article  CAS  PubMed  Google Scholar 

  74. SH Jee LE Boulware E Guallar I Suh LJ Appel ER Miller Suffix3rd (2005) ArticleTitleDirect, progressive association of cardiovascular risk factors with incident proteinuria: results from the Korea Medical Insurance Corporation (KMIC) study Arch Intern Med 165 2299–304 Occurrence Handle10.1001/archinte.165.19.2299 Occurrence Handle16246998

    Article  PubMed  Google Scholar 

  75. J Arnlov JC Evans JB Meigs TJ Wang CS Fox D Levy et al. (2005) ArticleTitleLow-grade albuminuria and incidence of cardiovascular disease events in nonhypertensive and nondiabetic individuals: the Framingham Heart Study Circulation 112 969–75 Occurrence Handle10.1161/CIRCULATIONAHA.105.538132 Occurrence Handle16087792

    Article  PubMed  Google Scholar 

  76. GF Watts S Herrmann GK Dogra DA Playford JD Best MA Thomas et al. (2001) ArticleTitleVascular function of the peripheral circulation in patients with nephrosis Kidney Int 60 182–9 Occurrence Handle1:STN:280:DC%2BD3MznslymsQ%3D%3D Occurrence Handle10.1046/j.1523-1755.2001.00785.x Occurrence Handle11422750

    Article  CAS  PubMed  Google Scholar 

  77. A Festa R D'Agostino G Howard L Mykkanen RP Tracy SM Haffner (2000) ArticleTitleInflammation and microalbuminuria in nondiabetic and type 2 diabetic subjects: the insulin resistance atherosclerosis study Kidney Int 58 1703–10 Occurrence Handle1:CAS:528:DC%2BD3cXntlylurc%3D Occurrence Handle10.1046/j.1523-1755.2000.00331.x Occurrence Handle11012904

    Article  CAS  PubMed  Google Scholar 

  78. JI Barzilay D Peterson M Cushman SR Heckbert JJ Cao C Blaum et al. (2004) ArticleTitleThe relationship of cardiovascular risk factors to microalbuminuria in older adults with or without diabetes mellitus or hypertension: the cardiovascular health study Am J Kidney Dis 44 25–34 Occurrence Handle10.1053/j.ajkd.2004.03.022 Occurrence Handle15211434

    Article  PubMed  Google Scholar 

  79. T Deckert B Feldt-Rasmussen K Borch-Johnsen T Jensen A Kofoed-Enevoldsen (1989) ArticleTitleAlbuminuria reflects widespread vascular damage. The Steno hypothesis Diabetologia 32 219–26 Occurrence Handle1:STN:280:DyaL1MzjvFSjtA%3D%3D Occurrence Handle10.1007/BF00285287 Occurrence Handle2668076

    Article  CAS  PubMed  Google Scholar 

  80. CD Stehouwer YM Smulders (2006) ArticleTitleMicroalbuminuria and risk for cardiovascular disease: analysis of potential mechanisms J Am Soc Nephrol 17 2106–11 Occurrence Handle1:CAS:528:DC%2BD28XosFalsbc%3D Occurrence Handle10.1681/ASN.2005121288 Occurrence Handle16825333

    Article  CAS  PubMed  Google Scholar 

  81. CD Stehouwer (2004) ArticleTitleEndothelial dysfunction in diabetic nephropathy: state of the art and potential significance for non-diabetic renal disease Nephrol Dial Transplant 19 778–81 Occurrence Handle10.1093/ndt/gfh015 Occurrence Handle15031329

    Article  PubMed  Google Scholar 

  82. MI Arcos CK Fujihara A Sesso EB de Almeida Prado MJ de Almeida Prado G de Nucci et al. (2000) ArticleTitleMechanisms of albuminuria in the chronic nitric oxide inhibition model Am J Physiol Renal Physiol 279 F1060–6 Occurrence Handle1:STN:280:DC%2BD3M%2FntlOkug%3D%3D Occurrence Handle10.1152/ajprenal.2000.279.6.F1060 Occurrence Handle11097624

    Article  CAS  PubMed  Google Scholar 

  83. M Sharma ET McCarthy VJ Savin EA Lianos (2005) ArticleTitleNitric oxide preserves the glomerular protein permeability barrier by antagonizing superoxide Kidney Int 68 2735–44 Occurrence Handle1:CAS:528:DC%2BD28XhslWjsw%3D%3D Occurrence Handle10.1111/j.1523-1755.2005.00744.x Occurrence Handle16316348

    Article  CAS  PubMed  Google Scholar 

  84. K Caglar MI Yilmaz A Sonmez E Cakir A Kaya C Acikel et al. (2006) ArticleTitleADMA, proteinuria, and insulin resistance in non-diabetic stage I chronic kidney disease Kidney Int 70 781–7 Occurrence Handle1:CAS:528:DC%2BD28XnvVyltLY%3D Occurrence Handle10.1038/sj.ki.5001632 Occurrence Handle16820789

    Article  CAS  PubMed  Google Scholar 

  85. D Fliser F Kronenberg JT Kielstein C Morath SM Bode-Boger H Haller et al. (2005) ArticleTitleAsymmetric dimethylarginine and progression of chronic kidney disease: the mild to moderate kidney disease study J Am Soc Nephrol 16 2456–61 Occurrence Handle1:CAS:528:DC%2BD2MXovVOku7Y%3D Occurrence Handle10.1681/ASN.2005020179 Occurrence Handle15930091

    Article  CAS  PubMed  Google Scholar 

  86. Y Matsumoto S Ueda S Yamagishi K Matsuguma R Shibata K Fukami et al. (2007) ArticleTitleDimethylarginine 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 1525–33 Occurrence Handle1:CAS:528:DC%2BD2sXls1Glu7g%3D Occurrence Handle10.1681/ASN.2006070696 Occurrence Handle17409314

    Article  CAS  PubMed  Google Scholar 

  87. EB Marliss S Chevalier R Gougeon JA Morais M Lamarche OA Adegoke et al. (2006) ArticleTitleElevations of plasma methylarginines in obesity and ageing are related to insulin sensitivity and rates of protein turnover Diabetologia 49 351–9 Occurrence Handle1:CAS:528:DC%2BD28XhtFWntb0%3D Occurrence Handle10.1007/s00125-005-0066-6 Occurrence Handle16369774

    Article  CAS  PubMed  Google Scholar 

  88. TH Jafar PC Stark CH Schmid M Landa G Maschio PE de Jong et al. (2003) ArticleTitleProgression of chronic kidney disease: the role of blood pressure control, proteinuria, and angiotensin-converting enzyme inhibition: a patient-level meta-analysis Ann Intern Med 139 244–52 Occurrence Handle1:CAS:528:DC%2BD3sXnt12kurs%3D Occurrence Handle10.7326/0003-4819-139-4-200308190-00006 Occurrence Handle12965979

    Article  CAS  PubMed  Google Scholar 

  89. P Ravani G Tripepi F Malberti S Testa F Mallamaci C Zoccali (2005) ArticleTitleAsymmetrical dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease: a competing risks modeling approach J Am Soc Nephrol 16 2449–55 Occurrence Handle1:CAS:528:DC%2BD2MXovVOku7k%3D Occurrence Handle10.1681/ASN.2005010076 Occurrence Handle15944335

    Article  CAS  PubMed  Google Scholar 

  90. DH Kang T Nakagawa L Feng RJ Johnson (2002) ArticleTitleNitric oxide modulates vascular disease in the remnant kidney model Am J Pathol 161 239–48 Occurrence Handle1:CAS:528:DC%2BD38Xlsl2ks7s%3D Occurrence Handle10.1016/S0002-9440(10)64175-2 Occurrence Handle12107108 Occurrence Handle1850677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. A Erdely L Wagner V Muller A Szabo C Baylis (2003) ArticleTitleProtection of Wistar Furth rats from chronic renal disease is associated with maintained renal nitric oxide synthesis J Am Soc Nephrol 14 2526–33 Occurrence Handle1:CAS:528:DC%2BD3sXnt1ahtrY%3D Occurrence Handle10.1097/01.ASN.0000086476.48686.7D Occurrence Handle14514730 Occurrence Handle2747486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. T Murohara T Asahara M Silver C Bauters H Masuda C Kalka et al. (1998) ArticleTitleNitric oxide synthase modulates angiogenesis in response to tissue ischemia J Clin Invest 101 2567–78 Occurrence Handle1:CAS:528:DyaK1cXjvVahs7w%3D Occurrence Handle10.1172/JCI1560 Occurrence Handle9616228 Occurrence Handle508846

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Nephrology, Department of Medicine, Kurume University School of Medicine, Kurume, 830-0011, Japan

    Seiji Ueda, Yuriko Matsumoto, Kei Fukami & Seiya Okuda

  2. Division of Cardiovascular Medicine, Department of Medicine, Kurume University School of Medicine, Kurume, Japan

    Sho-ichi Yamagishi

Authors
  1. Seiji Ueda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sho-ichi Yamagishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuriko Matsumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kei Fukami
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Seiya Okuda
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Seiya Okuda.

About this article

Cite this article

Ueda, S., Yamagishi, Si., Matsumoto, Y. et al. Asymmetric dimethylarginine (ADMA) is a novel emerging risk factor for cardiovascular disease and the development of renal injury in chronic kidney disease. Clin Exp Nephrol 11, 115–121 (2007). https://doi.org/10.1007/s10157-007-0471-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10157-007-0471-x

Key words

Search

Navigation