The Preventive Effect of Captopril on VEGF Expression in Streptozotocin-induced Diabetic Retiniopathy

당뇨병성 망막증에 있어서 Captopril에 의한 VEGF 발현 저하 효과

  • Bae, Chun-Sik (College of Veterinary Medicine, Chonnam National University) ;
  • Lim, Seul-Ki (College of Veterinary Medicine, Chonnam National University) ;
  • Park, Min-Jung (College of Veterinary Medicine, Chonnam National University) ;
  • Han, Ho-Jae (College of Veterinary Medicine, Chonnam National University) ;
  • Kim, Kye-Yeop (College of Health and Welfare, Dongshin University) ;
  • Jeong, Soo-Young (Jeonnam Development Institute for Korean Traditional Medicine) ;
  • Yoon, Kyung-Chul (Department of Ophthalmology, Chonnam National University, Medical School and Hospital) ;
  • Park, Soo-Hyun (College of Veterinary Medicine, Chonnam National University)
  • 배춘식 (전남대학교 수의과대학 바이오치료 산업인력 양성팀, 동물의학 연구소) ;
  • 임슬기 (전남대학교 수의과대학 바이오치료 산업인력 양성팀, 동물의학 연구소) ;
  • 박민정 (전남대학교 수의과대학 바이오치료 산업인력 양성팀, 동물의학 연구소) ;
  • 한호재 (전남대학교 수의과대학 바이오치료 산업인력 양성팀, 동물의학 연구소) ;
  • 김계엽 (동신대학교 보건 의료대학 물리치료학과) ;
  • 정수영 (전라남도 한방산업 진흥원) ;
  • 윤경철 (전남대학교 의과대학 안과학교실) ;
  • 박수현 (전남대학교 수의과대학 바이오치료 산업인력 양성팀, 동물의학 연구소)
  • Received : 2009.03.19
  • Accepted : 2009.06.23
  • Published : 2009.06.30

Abstract

Diabetic retinopathy is one of major complications of diabetes mellitus, which is associated with the dysfunction of retina. It has been reported that the onset of diabetic retinopathy is related to the activation of renin-angiotensin system (RAS). Angiotensin converting enzyme (ACE), which converts angiotensin I into angiotensin II, is a key component of RAS. Among many growth factors, vascualr endothelial growth factor (VEGF) is an important cytokine in the neovasculization of retina, which is a characteristics of diabetic retinopathy. However, the relationship between ACE and VEGF was not elucidated in diabetic retinopathy. Thus, this study was conducted to examine the protective effect of captopril, an ACE inhibitor, in the retina of streptozotocin (STZ)-treated diabetic rats. In present study, STZ-treated diabetic rats exhibited the increase of VEGF levels in serum and retina. The serum levels of VEGF in STZ-treated diabetic rats was not blocked by the treatment of captopril. However, the retina levels of VEGF in STZ-treated diabetic rats was blocked by the treatment of captopril, suggesting the local action of captopril in retina. Immunohistochemical analysis also revealed that the retina of STZ-treated diabetic rats manifested the increase of ganglion cell layers, outer nuclear layers, and inner nuclear layers, which were also prevented by the treatment of captopril. In conclusion, captopril prevented the expression of VEGF in the retina of STZ-treated diabetic rats.

당뇨병성 망막증의 당뇨병 합병증의 주요한 증상중의 하나로 망막의 구조적 기능적 변화를 초래한다. 레닌-안지오텐신 시스템은 당뇨병성 망막증의 발병에 주요한 역할을 담당하며 angiotensin I을 angiotensin II로 전환하는 데 담당하는 안지오텐신 전환 효소 (ACE)는 레닌-안지오텐신 시스템의 주요한 요소이다. VEGF는 실명을 일으키는 당뇨병성 망막증의 신생혈관 생성에 관여하는 주요한 인자로 알려져 있다. 따라서 본 연구에서는 당뇨병성 망막증의 발생 기전 중 하나로 최근 연구가 진행되고 있는 VEGF의 발현과 안지오텐신 전환 효소 억제제를 이용한 VEGF 발현 억제효과의 규명을 통해 당뇨병성 망막증의 예방에 ACE 억제제가 효과가 있는지 ACE 억제제인 captopril을 이용하여 알아보고자 하였다. 본 연구에서는 streptozotocin 처리시 혈청내 VEGF 농도는 증가하였으나 captopril (65 mg/kg) 치료에 의해 감소하지 않았다. 망막에서 관찰한 결과 당뇨군에서 VEGF mRNA 및 단백질 발현이 증가하였으며, 안지오텐신 전환 효소인 capto-pril에 의해서 차단되는 것으로 나타났다. 결론적으로 captopril은 1형 당뇨에 있어서 망막의 VEGF 발현 억제를 통해 망막 보호효과를 나타내고 있음을 알 수 있었다.

Keywords

References

  1. Bradford MM: A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72 : 248-254, 1976 https://doi.org/10.1016/0003-2697(76)90527-3
  2. Brugts JJ, den Uil CA, Danser AH, Boersma E: The renin-angiotensin-aldosterone system: approaches to guide angiotensinconverting enzyme inhibition in patients with coronary artery disease. Cardiology 112(4) : 303-312, 2008 https://doi.org/10.1159/000159124
  3. Cavusoglu AC, Bilgili S, Alaluf A, Doan A, Yilmaz F, Aslanca D, Karaca B, Yuksel B, Topaloglu E: Vascular endothelial growth factor level in the serum of diabetic patients with retinopathy. Ann Ophthalmol (Skokie) 39(3) : 205-208, 2007 https://doi.org/10.1007/s12009-007-0037-2
  4. Crawford TN, Alfaro DV 3rd, Kerrison JB, Jablon EP: Diabetic retinopathy and angiogenesis. Curr Diabetes Rev 5(1) : 8-13, 2009 https://doi.org/10.2174/157339909787314149
  5. Deshpande AD, Harris-Hayes M, Schootman M: Epidemiology of diabetes and diabetes-related complications. Phys Ther 88(11) : 1254-1264, 2008 https://doi.org/10.2522/ptj.20080020
  6. Ebrahimian TG, Tamarat R, Clergue M, Duriez M, Levy BI, Silvestre JS: Dual effect of angiotensin-converting enzyme inhibition on angiogenesis in type 1 diabetic mice. Arterioscler Thromb Vasc Biol 25(1) : 65-70, 2005
  7. Ejaz S, Chekarova I, Ejaz A, Sohail A, Lim CW: Importance of pericytes and mechanisms of pericyte loss during diabetes retinopathy. Diabetes Obes Metab 10(1) : 53-63, 2008
  8. Gariano RF, Gardner TW: Retinal angiogenesis in development and disease. Nature 438(7070) : 960-966, 2005 https://doi.org/10.1038/nature04482
  9. Hansson GK, Schwartz SM: Evidence for cell death in the vascular endothelium in vivo and in vitro. Am J Patho 112(3) : 278-286, 1983
  10. Kim JH, Kim JH, Yu YS, Cho CS, Kim KW: Blockade of angiotensin II attenuates VEGF-mediated blood-retinal barrier breakdown in diabetic retinopathy. J Cereb Blood Flow Metab 29(3) : 621-628, 2009 https://doi.org/10.1038/jcbfm.2008.154
  11. Ko SH, Lee WY, Lee JH, Kwon HS, Lee JM, Kim SR, Moon SD, Song KH, Han JH, Ahn YB, Yoo SJ, Son HY: Clinical characteristics of diabetic ketoacidosis in Korea over the past two decades. Diabet Med 22(4) : 466-469, 2005 https://doi.org/10.1111/j.1464-5491.2005.01450.x
  12. Korea Diabetes Association: Diabetic retinopathy. Clinical Diabetes 6(3) : 216-219, 2005
  13. Mycliwiec M, Balcerska A, Zorena K, Mycliwska J, Lipowski P, Raczyriska K: The role of vascular endothelial growth factor, tumor necrosis factor alpha and interleukin-6 in pathogenesis of diabetic retinopathy. Diabetes Res Clin Pract 79(1) : 141-146, 2008 https://doi.org/10.1016/j.diabres.2007.07.011
  14. Nakanishi Y, Nakamura M, Mukuno H, Kanamori A, Seigel GM, Negi A: Latanoprost rescues retinal neuro-glial cells from apoptosis by inhibiting caspase-3, which is mediated by p44/p42 mitogen-activated protein kinase. Exp Eye Res 83(5) : 1108-1117, 2006 https://doi.org/10.1016/j.exer.2006.05.018
  15. Novo G, Guttilla D, Fazio G, Cooper D, Novo S: The role of the renin-angiotensin system in atrial fibrillation and the therapeutic effects of ACE-Is and ARBS. Br J Clin Pharmacol 66(3) : 345-351, 2008 https://doi.org/10.1111/j.1365-2125.2008.03234.x
  16. Penn JS, Madan A, Caldwell RB, Bartoli M, Caldwell RW, Hartnett ME: Vascular endothelial growth factor in eye disease. Prog Retin Eye Res 27(4) : 331-371, 2008 https://doi.org/10.1016/j.preteyeres.2008.05.001
  17. Rodriguez-Fontal M, Alfaro V, Kerrison JB, Jablon EP: Ranibizumab for diabetic retinopathy. Curr Diabetes Rev 5(1) : 47-51, 2009 https://doi.org/10.2174/157339909787314239
  18. Saint-Geniez M, Maharaj AS, Walshe TE, Tucker BA, Sekiyama E, Kurihara T, Darland DC, Young MJ, D'Amore PA: Endogenous VEGF is required for visual function: evidence for a survival role on muller cells and photoreceptors. PLoS ONE 3(11) : e3554, 2008 https://doi.org/10.1371/journal.pone.0003554
  19. Sarlos S, Wilkinson-Berka JL: The renin-angiotensin system and the developing retinal vasculature. Invest Ophthalmol Vis Sci 46(3) : 1069-1077, 2005 https://doi.org/10.1167/iovs.04-0885
  20. Sugiyama T, Okuno T, Fukuhara M, Oku H, Ikeda T, Obayashi H, Ohta M, Fukui M, Hasegawa G, Nakamura N: Angiotensin II receptor blocker inhibits abnormal accumulation of advanced glycation end products and retinal damage in a rat model of type 2 diabetes. Exp Eye Res 85(3) : 406-412, 2007 https://doi.org/10.1016/j.exer.2007.06.008
  21. Tikellis C, Johnston CI, Forbes JM, Burns WC, Thomas MC, Lew RA, Yarski M, Smith AI, Cooper ME: Identification of angotensin converting enzyme 2 in the rodent retina. Curr Eye Res 29(6) : 419-427, 2004 https://doi.org/10.1080/02713680490517944
  22. van Bugenum MH, Polak BCP, Reichert-Thoen JWM, de Vries-Knoppert WAEJ, van Hinsbergh VWM, Tangelder GJ: Angiotensin converting enzyme inhibiting therapy is associated with lower vitreous vascular endothelial growth factor concentrations in patients with proliferative diabetic retinopathy. Diabetol 45 : 203-209, 2002 https://doi.org/10.1007/s00125-001-0747-8
  23. Wilkinson-Berka JL: Angiotensin and diabetic retinopathy. Int J Biochem Cell Biol 38(5-6) : 752-765, 2006 https://doi.org/10.1016/j.biocel.2005.08.002
  24. Yoon KH, Lee JH, Kim JW, Cho JH, Choi YH, Ko SH, Zimmet P, Son HY: Epidemic obesity and type 2 diabetes in Asia. Lancet 368 : 1681-1688, 2006 https://doi.org/10.1016/S0140-6736(06)69703-1
  25. Zhang X, Lassila M, Cooper ME, Cao Z: Retinal expression of vascular endothelial growth factor is mediated by angiotensin type 1 and type 2 receptors. Hypertension 43(2) : 276-281, 2004 https://doi.org/10.1161/01.HYP.0000113628.94574.0f