당뇨 쥐에서 Vitamin B6 (PLP)의 망막혈관누출 감소와 혈관내피성장인자의 억제 효과
Suppression of VEGF and Decrease in Vascular Leakage by Pyridoxal 5’-Phosphate in Diabetic Rats
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목적: STZ로 유발된 당뇨 쥐에서 Pyridoxal 5ʼ phosphate (PLP)가 당뇨망막병증에 미치는 영향을 알아보고자 했다. 대상과 방법: Sprague-Dawley 흰쥐(n=20)를 대상으로 하여 정상군 2마리를 제외한 18마리에서 당뇨를 유발시키고, 그 중 10마리에PLP를 투여하였다. PLP를 투여한 군 중 5마리에는 PLP 5 μg을, 5마리에는 50 μg를 각각 나누어서 투여하였다. PLP투여 3주 후혈액 내 호모시스테인 농도와 유리체 내 플루레신 농도를 측정한 후 안구를 적출하였다. 적출된 안구로 절편을 제작하여 혈관내피성장인자에 대한 면역조직화학염색을 시행하였고, 발현 양상을 비교하였다. 결과: 실험군에서의 호모시스테인과 플루레신 농도가 대조군에 비해서 유의하게 낮은 것으로 나타났다(p＜0.01). 혈관내피성장인자의발현도 실험군의 망막에서 발현이 감소되어 있는 것을 확인할 수 있었다. PLP의 투여 농도 변화에 대한 실험 결과에서는 유의한 상관관계를 보이지 않았다(p＞0.05). 결론: STZ로 유발된 당뇨 쥐에서 PLP의 투여는 망막 혈관 누출과 혈관내피성장인자의 발현을 억제하는 효과가 있다.
Abstract
Purpose: The authors of the present study investigated whether pyridoxal 5’-phosphate (PLP), an active coenzyme of vitamin B6, could inhibit the development of diabetic retinopathy in streptozotocin (STZ)-induced diabetic rats. Methods: Seven-week-old Spraque-Dawley rats (n = 20) were used in the present study. STZ (70 mg/kg) was injected intraperitoneally to induce diabetes. Blood glucose and body weight were monitored. Intraperitoneal injections of 5 μg and 50μg PLP were administered every two days from the second week of induced diabetes. During the third week of PLP injections,the concentration level of plasma homocysteine was measured. In addition, functional status was examined by vitreous fluorophotometer and anatomical status by vascular endothelial growth factor (VEGF) staining in the retina. Results: Based on vitreous fluorophotometry examination, the PLP injection group proved to have a lower level of fluorescein concentration in the vitreous. Additionally, immunohistochemical staining revealed down-regulation of VEGF expression in the PLP group. In addition, the PLP group had a lower plasma homocysteine concentration. However, an over-dosage injection of PLP did not appear to have any noticeable impact on the treatment of diabetes. Conclusions: PLP, an active coenzyme of vitamin B6, proved to have inhibitory effects on VEGF expression and vascular leakage in the diabetic rat retina.
참고문헌 (37)
- Amos AF, "The rising global burden of diabetes and its complications: estimates and projections to the year 2010", Diabet Med, 14(Suppl 5), pp.1~85 (1997)
- Marshall SM, "Prevention and early detection of vascular complications of diabetes", BMJ, 333, pp.475~480 (2006)
- Curtis TM, "Microvascular lesions of diabetic retinopathy: clues towards understanding pathogenesis?", Eye (Lond), 23, pp.1496~1508 (2009)
- Nishikawa T, "Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage", Nature, 404, pp.787~790 (2000)
- Brownlee M, "Biochemistry and molecular cell biology of diabetic complications", Nature, 414, pp.813~820 (2001)
- Van Hecke MV, "Inflammation and endothelial dysfunction are associated with retinopathy: the Hoorn Study", Diabetologia, 48, pp.1300~1306 (2005)
- Schram MT, "Markers of inflammation are cross-sectionally associated with microvascular complications and cardiovascular disease in type 1 diabetes-- the EURODIAB Prospective Complications Study", Diabetologia, 48, pp.370~378 (2005)
- Brazionis L, "Homocysteine and diabetic retinopathy", Diabetes Care, 31, pp.50~56 (2008)
- "Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group", Lancet, 352, pp.837~853 (1998)
- Yamagishi S, "Pigment-epithelium- derived factor suppresses expression of receptor for advanced glycation end products in the eye of diabetic rats", Ophthalmic Res, 39, pp.92~97 (2007)
- Kowluru RA, "Effect of long-term administration of alpha-lipoic acid on retinal capillary cell death and the development of retinopathy in diabetic rats", Diabetes, 53, pp.3233~3238 (2004)
- Bursell SE, "High-dose vitamin E supplementation normalizes retinal blood flow and creatinine clearance in patients with type 1 diabetes", Diabetes Care, 22, pp.1245~1251 (1999)
- 김응석, "황반부종을 동반한 비증식당뇨망막병증 환자에서 Anthocyanoside 복용 후 임상변화", 대한안과학회지, 49(10), pp.1629~1633 (2008), 대한안과학회
- 유선임, "실험적으로 유도된 당뇨유발 쥐 망막에서 리포산에 의한 혈관내피성장인자와 STAT3 억제효과", 대한안과학회지, 48(5), pp.715~724 (2007), 대한안과학회
- Okada M, "Effect of diabetes on vitamin B6 requirement in experimental animals", Diabetes Obes Metab, 1, pp.221~225 (1999)
- Toyota T, "The endocrine pancreas in pyridoxine deficient rats", Tohoku J Exp Med, 134, pp.331~336 (1981)
- Araki A, "Homocysteine and diabetic macroangiopathy", Nihon Rinsho, 64, pp.2153~2158 (2006)
- Cunha-Vaz JG, "Characterization of the early stages of diabetic retinopathy by vitreous fluorophotometry", Diabetes, 34, pp.53~59 (1985)
- Van Schaik HJ, "Evaluation of diabetic retinopathy by fluorophotometry. european concerted action on ocular fluorometry", Int Ophthalmol, 22, pp.97~104 (1999)
- Do carmo A, "Breakdown of the inner and outer blood retinal barrier in streptozotocin-induced diabetes", Exp Eye Res, 67, pp.569~575 (1998)
- Anis HH, "Effect of pyridoxine on the blood-retina barrier in experimentally induced hyperglycemia in rats", Can J Ophthalmol, 26, pp.354~357 (1991)
- Castro R, "Homocysteine metabolism, hyperhomocysteinaemia and vascular disease: an overview", J Inherit Metab Dis, 29, pp.3~20 (2006)
- Lominadze D, "Homocysteine causes cerebrovascular leakage in mice", Am J Physiol Heart Circ Physiol, 290, pp.1206~1213 (2006)
- Moshal KS, "Regulation of homocysteine-induced MMP-9 by ERK1", 2 pathway, 2006, pp.290, 883~891
- Aydemir O, "Plasma and vitreous homocysteine concentrations in patients with proliferative diabetic retinopathy", Retina, 28, pp.741~743 (2008)
- Brazionis L, "Homocysteine and diabetic retinopathy", Diabetes Care, 31, pp.50~56 (2008)
- Adamis AP, "Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy", Am J Ophthalmol, 118, pp.445~450 (1994)
- Aiello LP, "Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders", N Engl J Med, 331, pp.1480~1487 (1994)
- Mathews MK, "Vascular endothelial growth factor and vascular permeability changes in human diabetic retinopathy", Invest Ophthalmol Vis Sci, 38, pp.2729~2741 (1997)
- Higuchi O, "Aminophospholipid glycation and its inhibitor screening system: a new role of pyridoxal 5'-phosphate as the inhibitor", J Lipid Res, 47, pp.964~974 (2006)
- Padayatti PS, "High concentrations of glucose induce synthesis of argpyrimidine in retinal endothelial cells", Curr Eye Res, 23, pp.106~115 (2001)
- Canning P, "Inhibition of advanced glycation and absence of galectin-3 prevent blood-retinal barrier dysfunction during short-term diabetes", Exp Diabetes Res, 2007, pp.51837~ (2007)
- Moore TC, "The role of advanced glycation end products in retinal microvascular leukostasis", Invest Ophthalmol Vis Sci, 44, pp.4457~4464 (2003)
- Kiran SG, "Pyridoxal 5' phosphate protects islets against streptozotocin-induced beta-cell dysfunction-- in vitro and in vivo", Exp Biol Med (Maywood), 236, pp.456~465 (2011)
- Chen BH, "Advanced glycation end-products induce apoptosis involving the signaling pathways of oxidative stress in bovine retinal pericytes", Life Sci, 79, pp.1040~1048 (2006)
- Yamagishi S, "Advanced glycation endproducts accelerate calcification in microvascular pericytes", Biochem Biophys Res Commun, 258, pp.353~357 (1999)
- Stitt A, "The AGE inhibitor pyridoxamine inhibits development of retinopathy in experimental diabetes", Diabetes, 51, pp.2826~2832 (2002)