eNOS Glu298Asp Polymorphism and Endothelial Dysfunction in Patients with and without End-stage Renal Disease

Abstract

Background: Chronic kidney diseases are known to influence nitric oxide metabolites (NOx) and asymmetric dimethylarginine (ADMA), though the exact mechanism is still poorly understood. Aims: The purpose of the present study was to examine eNOS Glu298Asp gene polymorphism, plasma NOx and ADMA concentration in subjects with and without End-stage Renal Disease.  Study Design: Case-control study.  Methods: In this study, genotype distributions of Glu298Asp in exon 7 of the eNOS gene polymorphisms in 130 hemodialysis and 64 peritoneal dialysis patients were compared with 92 controls. NOx was measured by using the Griess reaction while arginine, ADMA and SDMA measurements were performed by HPLC. Genotyping for eNOS Glu298Asp polymorphism was detected with the polymerase chain reaction and/or polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique.  Results: When the genotype frequencies of TT and GT genes were compared between both groups, there was no detected statistically important difference, eventhough a TT genotype frequency was 27 (20.8%) versus 17 (26.6%), GT heterozygote genotype frequency was 52 (40%) versus 22 (34.4%), and GG homozygote genotype frequency was 51 (39.2%) versus 25 (39.1%), respectively (p>0.05). NOx, SDMA and ADMA concentrations were significantly elevated in subjects with hemodialysis patients as compared to their corresponding controls. Whereas nitrite was found to be significantly decreased in the patient with peritoneal dialysis. Conclusion: Not observed any connection between the Glu298Asp polymorphism in the eNOS gene and end-stage Renal Diseases in our study population under different dialysis treatments. However, higher ADMA and SDMA concentrations in subjects with ESRD support the existing hypothesis that NOx overproduction affects endothelial dysfunction. Thus, the reduction of ADMA and SDMA concentrations might play a protective role in ESRD patients.

Keywords

• eNOS Glu298Asp, endothelial dysfunction, end-stage renal disease

References

1. 1. Nakamura T, Sato E, Fujiwara N, Kawagoe Y, Ueda Y, Suzuki T, et al. Positive association of serum levels of advanced glycation end products and high mobility group box-1 with asymmetric dimethylarginine in nondiabetic chronic kidney disease patients. Metabolism 2009;58:1624-8. [CrossRef]
2. 2. Förstermann U. Oxidative stress in vascular disease: causes, defense mechanisms and potential therapies. Nat Clin Pract Cardiovasc Med 2008;5:338-49. [CrossRef]
3. 3. Harrison DG. Cellular and molecular mechanisms of endothelial cell dysfunction. J Clin Invest 1997;100:2153-7. [CrossRef]
4. 4. Jackson P, Loughrey CM, Lightbody JH, McNamee PT, Young IS. Effect of hemodialysis on total antioxidant capacity and serum antioxidants in patients with chronic renal failure. Clin Nephrol 1995;44:1135-8.
5. 5. Daschner M, Lenhartz H, Botticher D, Schaefer F, Wollschlager M, Mehls O, et al. Influence of dialysis on plasma lipid peroxidation products and antioxidant levels. Kidney Int 1996;50:1268-72. [CrossRef]
6. 6. Paradossi U, Ciofini E, Clerico A, Botto N, Biagini A, Colombo MG. Endothelial function and carotid intimamedia thickness in young healthy subjects among endothelial nitric oxide synthase Glu298Asp and T-786C polymorphisms. Stroke 2004;35:1305-9. [CrossRef]
7. 7. Naber CK, Baumgart D, Altmann C, Siffert W, Erbel R, Heusch G. eNOS 894T allele and coronary blood flow at rest and during adenosineinduced hyperemia. Am J Physiol Heart Circ Physiol 2001;281:1908-12.
8. 8. Hsu CN, Huang LT, Lau YT, Lin CY, Tain YL. The combined ratios of L-arginine and asymmetric and symmetric dimethylarginine as biomarkers in spontaneously hypertensive rats. Transl Res 2012;159:90-8. [CrossRef]

9. 9. Busch M, Fleck C, Wolf G, Stein G. Asymmetrical (ADMA) and symmetrical dimethylarginine (SDMA) as potential risk factors for cardiovascular and renal outcome in chronic kidney disease – possible candidates for paradoxical epidemiology? Amino Acids 2006;30:225-32. [CrossRef]
10. 10. Lu TM, Chung MY, Lin CC, Hsu CP, Lin SJ. Asymmetric dimethylarginine and clinical outcomes in chronic kidney disease. Clin J Am Soc Nephrol 2011;6:1566-72. [CrossRef]
11. 11. Szlachcic A, Krzysiek-Maczka G, Pajdo R, Targosz A, Magierowski M, Jasnos K, et al. The Impact of Asymmetric Dimethylarginine (ADMA), the Endogenous Nitric Oxide (NO) Synthase Inhibitor, to the Pathogenesis of Gastric Mucosal Damage. Curr Pharm Des 2013;19:90-7. [CrossRef]
12. 12. Young JM, Terrin N, Wang X, Greene T, Beck GJ, Kusek JW, et al. Asymmetric dimethylarginine and mortality in stages 3 to 4 chronic kidney disease. Clin J Am Soc Nephrol 2009;4:1115-20. [CrossRef]
13. 13. Tatematsu S, Wakino S, Kanda T, Homma K, Yoshioka K, Hasegawa K, et al. Role of nitric oxide-producing and -degrading pathways in coronary endothelial dysfunction in chronic kidney disease. J Am Soc Nephrol 2007;18:741-9. [CrossRef]
14. 14. Kerkeni M, Letaief A, Achour A, Miled A, Trivin F, Maaroufi K. Endothelial nitric oxide synthetase, methylenetetrahydrofolate reductase polymorphisms, and cardiovascular complications in Tunisian patients with nondiabetic renal disease. Clin Biochem 2009;42:958-64. [CrossRef]
15. 15. Thaha M, Pranawa, Yogiantoro M, Sutjipto, Sunarjo, Tanimoto M, et al. Association of endothelial nitric oxide synthase Glu298Asp polymorphism with end-stage renal disease. Clin Nephrol 2008;70:144-54. [CrossRef]
16. 16. Santos KG, Crispim D, Canani LH, Ferrugem PT, Gross JL, Roisenberg I. Association of eNOS gene polymorphisms with renal disease in Caucasians with type 2 diabetes. Diabetes Res Clin Pract 2011;91:353-62. [CrossRef]
17. 17. Wang D, Strandgaard S, Borresen ML, Luo Z, Connors SG, Yan Q, et al. Asymmetric dimethylarginine and lipid peroxidation products in early autosomal dominant polycystic kidney disease. Am J Kidney Dis 2008;51:184-91. [CrossRef]
18. 18. Zhou TB, Yin SS. Association of endothelial nitric oxide synthase Glu298Asp gene polymorphism with the risk of end-stage renal disease. Ren Fail 2013;35:573-8. [CrossRef]
19. 19. Zhou TB, Xu HL, Yin SS. Association between endothelial nitric oxide synthase Glu298Asp gene polymorphism and diabetic nephropathy susceptibility. Ren Fail 2013;35:173-8. [CrossRef]
20. 20. Yun Z, Yu-Ping Y, Zong-Wu T, Yang S, Fang Y, Fang S. Association of endothelial nitric oxide synthase gene polymorphisms with end-stage renal disease: a systematic review and meta-analysis. Ren Fail 2014;36:987-93. [CrossRef]