The Korean Journal of Medicine

  • 제85권5호
  • /
  • Pages.495-502
  • /
  • 2013
  • /
  • 1738-9364(pISSN)
  • /
  • 2289-0769(eISSN)
대한내과학회 (The Korean Association of Internal Medicine)
권호 표지
DOI QR코드

DOI QR Code

유지혈액투석 환자에서 안지오텐신 전환효소 유전자 다형성에 따른 sRAGE의 변화

Effects of Angiotensin-Converting Enzyme Polymorphism on Soluble Receptor for Advanced Glycation End-Products in Maintenance Hemodialysis Patients

  • 이강원 (원광대학교 의과대학 내과학교실) ;
  • 차정민 (원광대학교 의과대학 내과학교실) ;
  • 이유민 (원광대학교 의과대학 내과학교실) ;
  • 박석돈 (원광대학교 의과대학 면역질환유전체 연구소) ;
  • 송주흥 (원광대학교 의과대학 내과학교실) ;
  • 안선호 (원광대학교 의과대학 내과학교실)
  • Lee, Kang Won (Department of Internal Medicine, Wonkwang University College of Medicine) ;
  • Cha, Jeong Min (Department of Internal Medicine, Wonkwang University College of Medicine) ;
  • Lee, Yu Min (Department of Internal Medicine, Wonkwang University College of Medicine) ;
  • Park, Seok Don (Genome Research Center for Immune Disorder, Wonkwang University College of Medicine) ;
  • Song, Ju Hung (Department of Internal Medicine, Wonkwang University College of Medicine) ;
  • Ahn, Seon Ho (Department of Internal Medicine, Wonkwang University College of Medicine)
  • 투고 : 2012.05.04
  • 심사 : 2013.04.10
  • 발행 : 2013.11.01
⟨ 이전 논문 다음 논문 ⟩

초록

목적: 당화산물(AGE)은 당화산물 수용체(RAGE)에 작용하여 다양한 독성 효과를 일으키는데 일부 혈청에 순환하는 가용성 당화산물 수용체(sRAGE)는 체내에서 생기는 당화산물과 그 수용체 간의 작용을 억제하는 기능을 가지고 있다. 최근 안지오텐신 전환효소억제제(ACEI)가 당뇨 환자에서 당화산물 축적을 감소시키면서 혈청 sRAGE 농도를 증가시키는 것으로 보고되고 있어 저자들은 유지혈액투석 중인 환자에서 ACE 유전자 다형성에 따른 sRAGE의 변화를 알아보고자 본 연구를 시행하였다. 방법: 유지혈액투석 중인 105명의 환자를 대상으로 혈청 sRAGE와 여러 생화학적 지표들을 ACE 유전자형에 따라 비교 분석하였다. 결과: 대상 환자는 105명이었다(남자 55, 여자 50명, 평균 연령 $58.77{\pm}1.68$세, 당뇨 환자 46명, 비당뇨 환자 59명). 투석 기간 $62.39{\pm}9.5$개월, ACE 유전자형의 분포는 II형 56명(35.9%), ID형 29명(18.6%), DD형 20명(12.8%)이었다. 전체 혈액투석 환자에서 연령이 증가함에 따라 sRAGE 감소하였다(r = -0.24; p = 0.013). 투석 기간, CRP 및 24시간 소변량과 sRAGE는 상관성이 없었다. 연령, 투석 기간, 24시간 소변량을 공변량으로 처리한 후 유전자형에 따른 sRAGE를 분석하였다. 전체 대상 환자에서 sRAGE는 연령에 따라 영향을 받고 있지만(F = 5.38; p = 0.02), ACE 유전자형에 따라서는 유의한 차이가 없었다($3,872.80{\pm}237.11$ vs. $4,224.17{\pm}255.60pg/mL$; F = 0.53; p = 0.47). RAS 억제제를 사용하고 있는 당뇨 환자는 37명이었고 ACE 유전자 II형 18명, ID+DD형 19명이었다. 공분산분석을 시행한 결과, sRAGE 농도 차이는 연령에 따라 영향을 받고 있지만(F = 6.10; p = 0.02), ACE 유전자형에 따라서는 차이가 없었다(sRAGE $3,874.01{\pm}472.98$ vs. $4,114.69{\pm}429.26pg/mL$; F = 0.06; p = 0.80). 결론: 혈액투석 중인 환자에서 sRAGE 농도는 ACE 유전자 다형성에 따라서는 차이가 없었고 연령이 증가함에 따라 감소하였다.

Background/Aims: Advanced glycation end-products (AGEs) exert various toxic effects through the receptor for AGEs (RAGE). Soluble RAGE (sRAGE) is a naturally occurring inhibitor of AGE-RAGE. Recent studies have suggested that inhibition of angiotensin-converting enzyme (ACE) reduces the accumulation of AGEs in diabetes partly by increasing the production and secretion of sRAGE into the plasma. This report describes the relationship between sRAGE and ACE polymorphism in maintenance hemodialysis patients. Methods: The levels of sRAGE and advanced oxidation protein products (AOPPs) were assessed by enzyme-linked immunosorbent assay (ELISA), and ACE polymorphism was detected by PCR amplification. Results: The distributions of ACE genotypes in 105 hemodialysis patients were as follows: II, 56 (35.9%); ID, 29 (18.6%); and DD, 20 (12.8%). According to the ACE genotypes, the study group consisted of II (n = 56) and ID + DD group (n = 49). sRAGE was correlated with age (r = -0.24; p = 0.013). There were significant differences in sRAGE, AOPP, age, duration of dialysis, C-reactive protein, or 24-h urine volume between two genotype groups. There were no significant differences in sRAGE levels, even though the effect of age was treated as a covariate. Conclusions: Our findings suggested that sRAGE may be affected only by age, and not by ACE polymorphism in maintenance hemodialysis patients.

키워드

과제정보

연구 과제 주관 기관 : Ministry of Health and Welfare

참고문헌

  1. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy: the Collaborative Study Group. N Engl J Med 1993; 329:1456-1462. https://doi.org/10.1056/NEJM199311113292004
  2. Forbes JM, Cooper ME, Thallas V, et al. Reduction of the accumulation of advanced glycation end products by ACE inhibition in experimental diabetic nephropathy. Diabetes 2002;51:3274-3282. https://doi.org/10.2337/diabetes.51.11.3274
  3. Miyata T, van Ypersele de Strihou C, Ueda Y, et al. Angiotensin II receptor antagonists and angiotensin-converting enzyme inhibitors lower in vitro the formation of advanced glycation end products: biochemical mechanisms. J Am Soc Nephrol 2002;13:2478-2487. https://doi.org/10.1097/01.ASN.0000032418.67267.F2
  4. Forbes JM, Thorpe SR, Thallas-Bonke V, et al. Modulation of soluble receptor for advanced glycation end products by angiotensin-converting enzyme-1 inhibition in diabetic nephropathy. J Am Soc Nephrol 2005;16:2363-2372. https://doi.org/10.1681/ASN.2005010062
  5. Neeper M, Schmidt AM, Brett J, et al. Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins. J Biol Chem 1992;267: 14998-15004.
  6. Wendt T, Tanji N, Guo J, et al. Glucose, glycation, and RAGE: implications for amplification of cellular dysfunction in diabetic nephropathy. J Am Soc Nephrol 2003;14:1383-1395. https://doi.org/10.1097/01.ASN.0000065100.17349.CA
  7. Yonekura H, Yamamoto Y, Sakurai S, et al. Novel splice variants of the receptor for advanced glycation end-products expressed in human vascular endothelial cells and pericytes, and their putative roles in diabetes-induced vascular injury. Biochem J 2003;370(Pt 3):1097-1109. https://doi.org/10.1042/BJ20021371
  8. Schlueter C, Hauke S, Flohr AM, Rogalla P, Bullerdiek J. Tissue-specific expression patterns of the RAGE receptor and its soluble forms: a result of regulated alternative splicing? Biochim Biophys Acta 2003;1630:1-6. https://doi.org/10.1016/j.bbaexp.2003.08.008
  9. Wautier JL, Zoukourian C, Chappey O, et al. Receptormediated endothelial cell dysfunction in diabetic vasculopathy: soluble receptor for advanced glycation end products blocks hyperpermeability in diabetic rats. J Clin Invest 1996;97: 238-243. https://doi.org/10.1172/JCI118397
  10. Park L, Raman KG, Lee KJ, et al. Suppression of accelerated diabetic atherosclerosis by the soluble receptor for advanced glycation endproducts. Nat Med 1998;4:1025-1031. https://doi.org/10.1038/2012
  11. Goova MT, Li J, Kislinger T, et al. Blockade of receptor for advanced glycation end-products restores effective wound healing in diabetic mice. Am J Pathol 2001;159:513-525. https://doi.org/10.1016/S0002-9440(10)61723-3
  12. Falcone C, Emanuele E, D'Angelo A, et al. Plasma levels of soluble receptor for advanced glycation end products and coronary artery disease in nondiabetic men. Arterioscler Thromb Vasc Biol 2005;25:1032-1037. https://doi.org/10.1161/01.ATV.0000160342.20342.00
  13. Haas M, Yilmaz N, Schmidt A, et al. Angiotensin-converting enzyme gene polymorphism determines the antiproteinuric and systemic hemodynamic effect of enalapril in patients with proteinuric renal disease: Austrian Study Group of the Effects of Enalapril Treatment in Proteinuric Renal Disease. Kidney Blood Press Res 1998;21:66-69. https://doi.org/10.1159/000025845
  14. Felehgari V, Rahimi Z, Mozafari H, Vaisi-Raygani A. ACE gene polymorphism and serum ACE activity in Iranians type II diabetic patients with macroalbuminuria. Mol Cell Biochem 2011;346:23-30. https://doi.org/10.1007/s11010-010-0587-2
  15. Witko-Sarsat V, Friedlander M, Capeillere-Blandin C, et al. Advanced oxidation protein products as a novel marker of oxidative stress in uremia. Kidney Int 1996;49:1304-1313. https://doi.org/10.1038/ki.1996.186
  16. Evans AE, Poirier O, Kee F, et al. Polymorphisms of the angiotensin-converting-enzyme gene in subjects who die from coronary heart disease. Q J Med 1994;87:211-214.
  17. Hanford LE, Enghild JJ, Valnickova Z, et al. Purification and characterization of mouse soluble receptor for advanced glycation end products (sRAGE). J Biol Chem 2004;279: 50019-50024. https://doi.org/10.1074/jbc.M409782200
  18. Hudson BI, Harja E, Moser B, Schmidt AM. Soluble levels of receptor for advanced glycation endproducts (sRAGE) and coronary artery disease: the next C-reactive protein? Arterioscler Thromb Vasc Biol 2005;25:879-882. https://doi.org/10.1161/01.ATV.0000164804.05324.8b
  19. Rhee H, Song SH, Kwak IS, et al. An explorative analysis of secretory receptor for advanced glycation endproducts in primary focal segmental glomerulosclerosis. Clin Exp Nephrol 2012;14:589-595.
  20. Harris R. Angiotensin-converting enzyme inhibition in diabetic nephropathy: it's all the RAGE. J Am Soc Nephrol 2005;16:2251-2253. https://doi.org/10.1681/ASN.2005060595
  21. Tanaka N, Yonekura H, Yamagishi S, Fujimori H, Yamamoto Y, Yamamoto H. The receptor for advanced glycation end products is induced by the glycation products themselves and tumor necrosis factor-alpha through nuclear factorkappa B, and by 17beta-estradiol through Sp-1 in human vascular endothelial cells. J Biol Chem 2000;275:25781-25790. https://doi.org/10.1074/jbc.M001235200
  22. Yamagishi S, Takeuchi M, Matsui T, Nakamura K, Imaizumi T, Inoue H. Angiotensin II augments advanced glycation end product-induced pericyte apoptosis through RAGE overexpression. FEBS Lett 2005;579:4265-4270. https://doi.org/10.1016/j.febslet.2005.06.058
  23. Bohlender J, Franke S, Sommer M, Stein G. Advanced glycation end products: a possible link to angiotensin in an animal model. Ann N Y Acad Sci 2005;1043:681-684. https://doi.org/10.1196/annals.1333.078
  24. Parving HH, de Zeeuw D, Cooper ME, et al. ACE gene polymorphism and losartan treatment in type 2 diabetic patients with nephropathy. J Am Soc Nephrol 2008;19:771-779. https://doi.org/10.1681/ASN.2007050582
  25. Nakamura K, Yamagishi SI, Adachi H, et al. Serum levels of sRAGE, the soluble form of receptor for advanced glycation end products, are associated with inflammatory markers in patients with type 2 diabetes. Mol Med 2007;13:185-189.
  26. Basta G, Sironi AM, Lazzerini G, et al. Circulating soluble receptor for advanced glycation end products is inversely associated with glycemic control and S100A12 protein. J Clin Endocrinol Metab 2006;91:4628-4634. https://doi.org/10.1210/jc.2005-2559
  27. Kalousova M, Hodkova M, Kazderova M, et al. Soluble receptor for advanced glycation end products in patients with decreased renal function. Am J Kidney Dis 2006;47: 406-411. https://doi.org/10.1053/j.ajkd.2005.12.028