Betacellulin induces increased retinal vascular permeability in mice.
Betacellulin induces increased retinal vascular permeability in mice.
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DOI：
10.1371/journal.pone.0013444
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发表时间：
2010-10-18
期刊：
影响因子：
3.7
通讯作者：
Folkman J
中科院分区：
文献类型：
--
作者：
Anand-Apte B;Ebrahem Q;Cutler A;Farage E;Sugimoto M;Hollyfield J;Folkman J
糖尿病性黄斑病变是2型糖尿病患者视力丧失的主要原因，其特征是视网膜血管的高通透性，随后形成黄斑水肿和硬渗出物。高血糖的程度和糖尿病的持续时间被认为是视网膜并发症的良好预测指标。干预研究已经确定，虽然糖尿病的强化治疗减少了增殖性糖尿病视网膜病变的发展，但与严重低血糖的风险增加2至3倍有关。因此，我们假设需要确定下游的血糖靶点，这些靶点可以诱导视网膜血管通透性，从而可以靶向治疗，而不会带来与高血糖强化治疗相关的额外风险。Betacellulin是一个32 kD的表皮生长因子家族成员，具有视网膜色素上皮细胞的有丝分裂特性。这使我们假设β细胞蛋白在糖尿病相关的视网膜血管并发症中的作用。在这项研究中，我们使用小鼠糖尿病模型，证明糖尿病小鼠视网膜血管通透性增强，同时视网膜中可溶性β细胞蛋白（s-Btc）的表达增加。玻璃体内注射可溶性β -纤维素蛋白诱导正常血糖和高血糖小鼠视网膜血管通透性。对糖尿病视网膜病变患者的视网膜进行Western blot分析，发现活性可溶性β细胞素增加。此外，在糖尿病小鼠和人类的视网膜中发现了A崩解素和金属蛋白酶(ADAM)-10水平的增加，ADAM -10在β细胞蛋白的切割中起作用。这些结果提示视网膜中过量的β细胞蛋白可能与糖尿病性黄斑水肿的发病机制有关。
Diabetic maculopathy, the leading cause of vision loss in patients with type 2 diabetes, is characterized by hyper-permeability of retinal blood vessels with subsequent formation of macular edema and hard exudates. The degree of hyperglycemia and duration of diabetes have been suggested to be good predictors of retinal complications. Intervention studies have determined that while intensive treatment of diabetes reduced the development of proliferative diabetic retinopathy it was associated with a two to three-fold increased risk of severe hypoglycemia. Thus we hypothesized the need to identify downstream glycemic targets, which induce retinal vascular permeability that could be targeted therapeutically without the additional risks associated with intensive treatment of the hyperglycemia. Betacellulin is a 32 kD member of the epidermal growth factor family with mitogenic properties for the retinal pigment epithelial cells. This led us to hypothesize a role for betacellulin in the retinal vascular complications associated with diabetes. In this study, using a mouse model of diabetes, we demonstrate that diabetic mice have accentuated retinal vascular permeability with a concomitant increased expression of a cleaved soluble form of betacellulin (s-Btc) in the retina. Intravitreal injection of soluble betacellulin induced retinal vascular permeability in normoglycemic and hyperglycemic mice. Western blot analysis of retinas from patients with diabetic retinopathy showed an increase in the active soluble form of betacellulin. In addition, an increase in the levels of A disintegrin and metalloproteinase (ADAM)-10 which plays a role in the cleavage of betacellulin was seen in the retinas of diabetic mice and humans. These results suggest that excessive amounts of betacellulin in the retina may contribute to the pathogenesis of diabetic macular edema.
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影响因子：
--
作者：
KLEIN, R;KLEIN, BEK;DEMETS, DL
通讯作者：
DEMETS, DL
影响因子：
2
作者：
Miyagawa, J;Hanafusa, T;Matsuzawa, Y
通讯作者：
Matsuzawa, Y
影响因子：
16.2
作者：
Keenan, Hillary A.;Costacou, Tina;King, George L.
通讯作者：
King, George L.
DOI：
10.1152/ajpendo.00120.2003
发表时间：
2003-09-01
影响因子：
5.1
作者：
Li, L;Seno, M;Kojima, I
通讯作者：
Kojima, I
影响因子：
4.4
作者：
Gao, Ben-Bo;Chen, Xiaohong;Feener, Edward P.
通讯作者：
Feener, Edward P.