Glutaredoxin regulates nuclear factor κ-B and intercellular adhesion molecule in Muller cells -: Model of diabetic retinopathy
Glutaredoxin regulates nuclear factor κ-B and intercellular adhesion molecule in Muller cells -: Model of diabetic retinopathy
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DOI：
10.1074/jbc.m610863200
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发表时间：
2007-04-27
影响因子：
4.8
通讯作者：
Mieyal, John J.
中科院分区：
文献类型：
--
作者：
Shelton, Melissa D.;Kern, Timothy S.;Mieyal, John J.
可逆s -谷胱甘肽化的蛋白质是氧化还原信号和细胞防御氧化应激的焦点。这种翻译后修饰改变了蛋白质的功能，其逆转（去谷胱甘肽化）是由一种硫二硫氧化还原酶glutaredoxin （GRx，硫转移酶）特异性和有效地催化的。我们假设谷胱甘肽的变化可能在糖尿病视网膜病变（一种以氧化应激为特征的疾病）的发展中起重要作用。事实上，GRx蛋白和活性在链脲佐菌素糖尿病大鼠的视网膜匀浆中增加。此外，将大鼠视网膜Muller细胞（rMC-1）在正常葡萄糖（5mm）或糖尿病样葡萄糖（25mm）培养基中孵育，与硫氧还蛋白（另一种硫硫二硫氧化还原酶系统）相比，GRx选择性上调。在类似的条件下，NF-kappa B （p50-p65）易位到细胞核，NF-kappa B的转录产物ICAM-1（细胞间粘附分子-1）的表达增加。促炎ICAM-1在糖尿病视网膜中升高，与视网膜病变的发病机制有关。为了评估GRx在介导这些变化中的作用，在正常葡萄糖条件下，通过感染腺病毒GRx1构建体（Ad-GRx）， rmc -1细胞内GRx含量和活性独立增加。rMC-1细胞表现出腺病毒浓度依赖性的GRx升高，NF-kappa B核易位、NF-kappa B荧光素酶报告活性和ICAM-1表达相应升高。在高糖条件下，通过小干扰RNA阻断rMC-1细胞中GRx1的增加可阻止ICAM-1表达的增加。这些数据表明，glutaredoxin在视网膜胶质细胞中的氧化还原调节受到高血糖的干扰，导致nf - κ B活化和促炎反应。因此，GRx可能是抑制糖尿病视网膜病变的一个新的治疗靶点。
Reversible S-glutathionylation of proteins is a focal point of redox signaling and cellular defense against oxidative stress. This post-translational modification alters protein function, and its reversal ( deglutathionylation) is catalyzed specifically and efficiently by glutaredoxin ( GRx, thioltransferase), a thioldisulfide oxidoreductase. We hypothesized that changes in glutaredoxin might be important in the development of diabetic retinopathy, a condition characterized by oxidative stress. Indeed, GRx protein and activity were increased in retinal homogenates from streptozotocin-diabetic rats. Also, incubation of rat retinal Muller cells ( rMC-1) in normal glucose ( 5 mM) or diabetic-like glucose ( 25 mM) medium led to selective up-regulation of GRx in contrast to thioredoxin, the other thioldisulfide oxidoreductase system. Under analogous conditions, NF-kappa B ( p50-p65) translocated to the nucleus, and expression of ICAM-1 ( intercellular adhesion molecule-1), a transcriptional product of NF-kappa B, increased. Proinflammatory ICAM-1 is increased in diabetic retinae, and it is implicated in pathogenesis of retinopathy. To evaluate the role of GRx in mediating these changes, intracellular GRx content and activity in rMC-1cells were increased independently under normal glucose via infection with an adenoviral GRx1 construct ( Ad-GRx). rMC-1 cells exhibited adenovirus concentration-dependent increases in GRx and corresponding increases in NF-kappa B nuclear translocation, NF-kappa B luciferase reporter activity, and ICAM-1 expression. Blocking the increase in GRx1 via small interfering RNA in rMC-1 cells in high glucose prevented the increased ICAM-1 expression. These data suggest that redox regulation by glutaredoxin in retinal glial cells is perturbed by hyperglycemia, leading to NF-kappa B activation and a pro-inflammatory response. Thus, GRx may represent a novel therapeutic target to inhibit diabetic retinopathy.