Dimethylarginine Dimethylaminohydrolase 2 Gene Polymorphism and Its Association with Asymmetrical Dimethyl Arginine in Hemodialyzed Patients

Mochamad Yusuf, Mochammad Thaha, Raden Mohammad Yogiarto, Muhammad Aminuddin, Raden Mohammad Yogiantoro, Retno Handajani, Yasuhiko Tomino

Cardiology and Vascular Medicine Department, Faculty of Medicine, Airlangga University, Surabaya, Indonesia.
Division of Nephrology, Departement of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan..
Nephrology-Hypertension Division, Internal Medicine Departement, Faculty of Medicine, Airlangga University, Surabaya, Indonesia.
Tropical Disease Center, Airlangga University, Surabaya, Indonesia..

DOI: 10.4236/ojneph.2013.31013                

Abstract

Introduction:Patients with CKD have elevated plasma levels of Asymmetrical Dimethyl Arginine (ADMA), impaired EDRF/NO responses in isolated resistance vessels, and a marked increase in the frequency of cardiovascular events that are predicated by plasma levels of ADMA. ADMA is considered as a risk factor for endothelial dysfunction, progression of chronic kidney disease and a marked increase in the frequency of cardiovascular events that are predicated by plasma levels of ADMA. Elevated ADMA in CKD have been related to a combination of a reduced renal ADMA excretion and a reduced catabolism of ADMA by dimethylarginine dimethylaminohydrolase (DDAH). The current study was undertaken to determine whether there is a correlation between ADMA and SNPs at -449 DDAH 2.Subjects and Methods :It was a cross sectional analytic study, 56 hemodialysis patients and 30 healthy individuals were enrolled. Based on its etiology, HD patients group was further divided in to hypertension (HT) subgroup and non-HT subgroup. Genotyping of the polymorphisms was performed using PCR-based SNP detection methods based on 5’-exonuclease activity assays for rs805305.Results :Heterozygotes were observed as the most abundant genotypes in both groups, followed by GG genotype in the HD patients (30%) and CC (27%) healthy individuals. Among the HT subgroup, the mean plasma levels of ADMA were sequentially higher from genotypes CC, G/C and GG (p = 0.037). Further multiple comparisons between groups using post hoc test showed results that genotype GG and CC were different at 0.05 level of significance. These findings were not found among non HT subgroup.Conclusion: Genetic variation in the DDAH 2 genes is significantly associated with serum ADMA levels in hypertensive HD patients. We observed that carriage of a G at position -449 in the promoter region of the DDAH 2 gene is associated with higher ADMA levels.

Keywords

ADMA; DDAH; Gene Polymorphism

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	M. Fujisawa, R. Haramaki, H. Miyazaki, T. Imaizumi and S. Okuda, “Role of Lipoprotein (a) and TGF-β1 in Atherosclerosis of Hemodialysis Patients,” Journal of the American Society of Nephrology, Vol. 11, No. 10, 2000, pp. 1889-1895.
[2]	A. Lindner, B. Charra, D. Sherrard and B. Scribner, “Accelerated Atherosclerosis in Prolonged Maintenance Hemodialysis,” New England Journal of Medicine, Vol. 290, No. 13, 1974, pp. 697-701.
[3]	K. Ma, E. Greene and L. Raij, “Cardiovascular Risk Factors in Chronic Renal Failure and Hemodialysis Populations,” American Journal of Kidney Diseases, Vol. 19, No. 6, 1992, pp. 505-513.
[4]	J. Cooke and V. Dzau, “Derangements of the Nitric Oxide Synthase Pathway, L-Arginine, and Cardiovascular Diseases,” Circulation, Vol. 96, No. 2, 1997, pp. 379-382.
[5]	A. Ito, P. S. Tsao, S. Adimoolam, M. Kimoto, T. Ogawa and J. P. Cooke, “Novel Mechanism for Endothelial Dysfunction: Dysregulation of Dimethylarginine Dimethylaminohydrolase,” Circulation, Vol. 99, No. 24, 1999, pp. 3092-3095.
[6]	R. M. J. Palmer, A. G. Ferrige and S. Moncada, “Nitric Oxide Release Accounts for the Biological Activity of Endothelium-Derived Relaxing Factor,” Nature, Vol. 327, 1987, pp. 524-526. doi:10.1038/327524a0
[7]	A. J. Pope, K. Karrupiah, P. N. Kearns, Y. Xia and A. J. Cardounel, “Role of Dimethylarginine Dimethylaminohydrolases in the Regulation of Endothelial Nitric Oxide Production,” Journal of Biological Chemistry, Vol. 284, No. 51, 2009, pp. 35338-35347.
[8]	C. Antoniades, C. Shirodaria, P. Leeson, A. Antonopoulos, N. Warrick, T. Van-Assche, et al., “Association of Plasma Asymmetrical Dimethylarginine (ADMA) with Elevated Vascular Superoxide Production and Endothelial Nitric Oxide Synthase Uncoupling: Implications for Endothelial Function in Human Atherosclerosis,” European Heart Journal, Vol. 30, No. 9, 2009, pp. 1142-1150.
[9]	R. Maas, K. Quitzau, E. Schwedhelm, L. Spieker, W. Rafflenbeul, A. Steenpass, et al., “Asymmetrical Dimethylarginine (ADMA) and Coronary Endothelial Function in Patients with Coronary Artery Disease and Mild Hypercholesterolemia,” Atherosclerosis, Vol. 191, No. 1, 2007, pp. 211-219.
[10]	F. Palm, M. L. Onozato, Z. Luo and C. S. Wilcox, “Dimethylarginine Dimethylaminohydrolase (DDAH): Ex- pression, Regulation, and Function in the Cardiovascular and Renal Systems,” Heart and Circulatory Physiology: American Journal of Physiology, Vol. 293, No. 6, 2007, pp. H3227-H3245.
[11]	C. Tran, J. Leiper and P. Vallance, “The DDAH/ADMA/ NOS Pathway,” Atherosclerosis Supplements, Vol. 4, No. 4, 2003, pp. 33-40.
[12]	R. Ryan, J. Thornton, E. Duggan, E. McGovern, M. J. O’Dwyer, A. W. Ryan, et al., “Gene Polymorphism and Requirement for Vasopressor Infusion after Cardiac Surgery,” Annals of Thoracic Surgery, Vol. 82, No. 3, 2006, pp. 895-901.
[13]	M. O’Dwyer, F. Dempsey, V. Crowley, D. Kelleher, R. McManus and T. Ryan, “Septic Shock Is Correlated with Asymmetrical Dimethyl Arginine Levels, Which May Be Influenced by a Polymorphism in the Dimethylarginine Dimethylaminohydrolase II Gene: A Prospective Observational Study,” Critical Care, Vol. 10, No. 5, 2006, p. R139.
[14]	R. Maas, “Pharmacotherapies and Their Influence on Asymmetric Dimethylargine (ADMA),” Vascular Medicine, Vol. 1, Suppl. 1, 2005, pp. S49-S57.
[15]	M. Thaha, Widodo, M. Yogiantoro and Y. Tomino, “Intravenous N-Acetylcysteine during Hemodialysis Reduces Asymmetric Dimethylarginine Levels in End-Stage Renal Disease Patients,” Clinical Nephrology, Vol. 69, No. 1, 2008, pp. 24-32.
[16]	M. Thaha, M. Yogiantoro and Y. Tomino, “Intravenous N-Acetylcysteine during Haemodialysis Reduces the Plasma Concentration of Homocysteine in Patients with End-Stage Renal Disease,” Clinical Drug Investigation, Vol. 26, 2006, pp. 195-202.
[17]	L. Jones, C. Tran, J. Leiper, A. Hingorani and P. Vallance, “Common Genetic Variation in a Basal Promoter Element Alters DDAH 2 Expression in Endothelial Cells,” Biochemical and Biophysical Research Communications, Vol. 310, No. 3, 2003, pp. 836-843.
[18]	R. Maas, J. Erdmann, N. Luneburg, J. Stritzke, E. Schwedhelm, C. Meisinger, et al., “Polymorphisms in the Promoter Region of the Dimethylarginine Dimethylaminohydrolase 2 Gene Are Associated with Prevalence of Hypertension,” Pharmacological Research, Vol. 60, No. 6, 2009, pp. 488-493.
[19]	J. Wang, A. Sim, X. Wang, C. Salonikas, D. Naidoo and D. Wilcken, “Relations between Plasma Asymmetric Dimethylarginine (ADMA) and Risk Factors for Coronary Disease,” Atherosclerosis, Vol. 184, No. 2, 2006, pp. 383-388.
[20]	P. Vallance and J. Leiper, “Asymmetric Dimethylarginine and Kidney Disease—Marker or Mediator?” Journal of the American Society of Nephrology, Vol. 16, No. 8, 2005, pp. 2254-2256.
[21]	J. T. Kielstein, S. R. Salpeter, S. M. Bode-Boeger, J. P. Cooke and D. Fliser, “Symmetric Dimethylarginine (SDMA) as Endogenous Marker of Renal Function—A Meta-Analysis,” Nephrology Dialysis Transplantation, Vol. 21, No. 9, 2006, pp. 2446-2451.
[22]	V. Achan, M. Broadhead, M. Malaki, G. Whitley, J. Leiper, R. MacAllister, et al., “Asymmetric Dimethylarginine Causes Hypertension and Cardiac Dysfunction in Humans and Is Actively Metabolized by Dimethylarginine Dimethylaminohydrolase,” Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 23, No. 8, 2003, pp. 1455-1459.
[23]	M. Feng, L. Liu, Z. Guo and Y. Xiong, “Gene Transfer of Dimethylarginine Dimethylaminohydrolase-2 Improves the Impairments of DDAH/ADMA/NOS/NO Pathway in Endothelial Cells Induced by Lysophosphatidylcholine,” European Journal of Pharmacology, Vol. 584, No. 1, 2008, pp. 49-56.
[24]	H. Dayoub, V. Achan, S. Adimoolam, J. Jacobi, M. C. Stuehlinger, B.-Y. Wang, et al., “Dimethylarginine Dimethylaminohydrolase Regulates Nitric Oxide Synthesis,” Circulation, Vol. 108, No. 24, 2003, pp. 3042-3047.
[25]	J. Leiper, J. Santa Maria, A. Chubb, R. MacAllister, I. Charles, G. Whitley, et al., “Identification of Two Human Dimethylarginine Dimethylaminohydrolases with Distinct Tissue Distributions and Homology with Microbial Arginine Deiminases,” Biochemical Journal, Vol. 341, 1999, pp. 209-214. doi:10.1042/0264-6021:3430209
[26]	J. Leiper and M. Nandi, “The Therapeutic Potential of Targeting Endogenous Inhibitors of Nitric Oxide Synthesis,” Nature Reviews Drug Discovery, Vol. 10, No. 4, 2011, pp. 277-291.
[27]	A. Tojo, W. Welch, V. Bremer, M. Kimoto, K. Kimura, M. Omata, et al., “Colocalization of Demethylating Enzymes and NOS and Functional Effects of Methylarginines in Rat Kidney,” Kidney International, Vol. 52, No. 6, 1997, pp. 1593-1601.
[28]	M. E. Widlansky, N. Gokce, J. F. Keaney Jr. and J. A. Vita, “The Clinical Implications of Endothelial Dysfunction,” Journal of the American College of Cardiology, Vol. 42, No. 7, 2003, pp. 1149-1160.
[29]	N. Dhalla, R. Temsah and T. Netticadan, “Role of Oxidative Stress in Cardiovascular Diseases,” Journal of Hypertension, Vol. 18, No. 6, 2000, pp. 655-673.
[30]	C. Tran, M. Fox, P. Vallance and J. Leiper, “Chromosomal Localization, Gene Structure, and Expression Pattern of DDAH 1: Comparison with DDAH 2 and Implications for Evolutionary Origins,” Genomics, Vol. 68, No. 1, 2000, pp. 101-105.
[31]	A. Ito, K. Egashira, T. Narishige, K. Muramatsu and A. Takeshita, “Renin-Angiotensin System Is Involved in the Mechanism of Increased Serum Asymmetric Dimethylarginine in Essential Hypertension,” Japanese Circulation Journal, Vol. 65, No. 9, 2001, pp. 775-778.
[32]	F. Perticone, A. Sciacqua, R. Maio, M. Perticone, R. Maas, R. H. Boger, et al., “Asymmetric Dimethylarginine, L-Arginine, and Endothelial Dysfunction in Essential Hypertension,” Journal of the American College of Cardiology, Vol. 46, No. 3, 2005, pp. 518-523.
[33]	J. Leiper and P. Vallance, “New Tricks from an Old Dog : Nitric Oxide-Independent Effects of Dimethylarginine Dimethylaminohydrolase,” Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 26, No. 7, 2006, pp. 1419-1420.
[34]	T. Ogawa, M. Kimoto and K. Sasaoka, “Purification and Properties of a New Enzyme, NG,NG-Dimethylarginine Dimethylaminohydrolase, from Rat Kidney,” Journal of Biological Chemistry, Vol. 264, No. 17, 1989, pp. 10205-10209.
[35]	T. Teerlink, “ADMA Metabolism and Clearance,” Vascular Medicine, Vol. 1, Suppl. 1, 2005, pp. S73-S81.
[36]	J. Jacobi, K. Sydow, G. von Degenfeld, Y. Zhang, H. Dayoub, B. Wang, et al., “Overexpression of Dimethylarginine Dimethylaminohydrolase Reduces Tissue Asymmetric Dimethylarginine Levels and Enhances Angiogenesis,” Circulation, Vol. 111, No. 11, 2005, pp. 1431- 1438.
[37]	C. Smith, G. Birdsey, S. Anthony, F. Arrigoni, J. Leiper and P. Vallance, “Dimethylarginine Dimethylaminohydrolase Activity Modulates ADMA Levels, VEGF Expression, and Cell Phenotype,” Biochemical and Biophysical Research Communications, Vol. 308, No. 4, 2003, pp. 984-989.
[38]	V. Achan, C. T. L. Tran, F. Arrigoni, G. S. J. Whitley, J. M. Leiper and P. Vallance, “All-Trans-Retinoic Acid Increases Nitric Oxide Synthesis by Endothelial Cells,” Circulation Research, Vol. 90, No. 7, 2002, pp. 764-769.
[39]	R. H. BÖger, S. M. Bode-BÖger, K. Sydow, D. D. Heistad and S. R. Lentz, “Plasma Concentration of Asymmetric Dimethylarginine, an Endogenous Inhibitor of Nitric Oxide Synthase, Is Elevated in Monkeys with Hyperhomocyst(e)inemia or Hypercholesterolemia,” Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 20, No. 6, 2000, pp. 1557-1564.