Differential expression of neuregulin-1 isoforms and downregulation of erbin are associated with Erb B2 receptor activation in diabetic peripheral neuropathy.
Differential expression of neuregulin-1 isoforms and downregulation of erbin are associated with Erb B2 receptor activation in diabetic peripheral neuropathy.
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DOI：
10.1186/2051-5960-1-39
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发表时间：
2013-07-17
影响因子：
7.1
通讯作者：
Dobrowsky RT
中科院分区：
文献类型：
--
作者：
Pan P;Dobrowsky RT
异常的神经元/神经胶质细胞相互作用可导致多种神经退行性疾病，我们以前已经证明，增强激活的Erb B2，这是表皮生长因子受体（EGFR）家族的成员，可有助于糖尿病周围神经病变（DPN）的发展。在外周神经中，ErB B受体被神经调节蛋白-1（NRG 1）家族的各种成员激活，包括NRG 1 I型、NRG 1 II型和NRG 1 III型，以调节雪旺细胞（SC）的生长、迁移、分化和去分化。或者，Erb B2活性可以通过与Erb B2相互作用蛋白erbin的结合来负调控。由于糖尿病对周围神经中NRG 1亚型和erbin表达的影响尚不清楚，因此本研究确定NRG 1亚型和erbin的变化是否与DPN中Erb B2信号的改变有关。Swiss韦伯斯特小鼠用链脲佐菌素（STZ）使其患糖尿病，并在糖尿病12周后用Erb B2活化的抑制剂厄洛替尼治疗。抑制Erb B2信号部分逆转了DPN的几个病理生理方面，包括明显的感觉痛觉减退、神经传导速度缺陷和表皮神经纤维神经支配减少。我们还观察到在糖尿病早期阶段，糖尿病腓肠神经中NRG 1 III型水平降低，但NRG 1 I型水平升高。随着疾病的进展，我们检测到糖尿病小鼠erbin表达减少，MAPK通路活性增强。抑制Erb B2受体可抑制糖尿病腓肠神经MAPK通路活性。这些结果支持高血糖可能通过破坏NRG 1亚型之间的平衡，降低erbin的表达并相应地激活MAPK通路来损害NRG 1/Erb B2信号传导。总之，不平衡的NRG 1亚型和下调的erbin可能导致DPN发展中Erb B2信号传导失调。
Aberrant neuron/glia interactions can contribute to a variety of neurodegenerative diseases and we have previously demonstrated that enhanced activation of Erb B2, which is a member of the epidermal growth factor receptor (EGFR) family, can contribute to the development of diabetic peripheral neuropathy (DPN). In peripheral nerves, Erb B receptors are activated by various members of the neuregulin-1 (NRG1) family including NRG1 Type I, NRG1 Type II and NRG1 Type III to regulate Schwann cell (SC) growth, migration, differentiation and dedifferentiation. Alternatively, Erb B2 activity can be negatively regulated by association with the Erb B2-interacting protein, erbin. Since the effect of diabetes on the expression of NRG1 isoforms and erbin in peripheral nerve are unknown, the current study determined whether changes in NRG1 isoforms and erbin may be associated with altered Erb B2 signaling in DPN. Swiss Webster mice were rendered diabetic with streptozotocin (STZ) and after 12 weeks of diabetes, treated with erlotinib, an inhibitor of Erb B2 activation. Inhibition of Erb B2 signaling partially reversed several pathophysiologic aspects of DPN including a pronounced sensory hypoalgesia, nerve conduction velocity deficits and the decrease in epidermal nerve fiber innervation. We also observed a decrease of NRG1 Type III but an increase of NRG1 Type I level in diabetic sural nerves at early stage of diabetes. With disease progression, we detected reduced erbin expression and enhanced MAPK pathway activity in diabetic mice. Inhibition of Erb B2 receptor suppressed MAPK pathway activity in treated-diabetic sural nerves. These results support that hyperglycemia may impair NRG1/Erb B2 signaling by disrupting the balance between NRG1 isoforms, decreasing the expression of erbin and correspondingly activating the MAPK pathway. Together, imbalanced NRG1 isoforms and downregulated erbin may contribute to the dysregulation of Erb B2 signaling in the development of DPN.
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影响因子：
7.4
作者：
Johnson MS;Ryals JM;Wright DE
通讯作者：
Wright DE
影响因子：
7.8
作者：
Bao, JX;Wolpowitz, D;Role, LW;Talmage, DA
通讯作者：
Talmage, DA
DOI：
10.1530/joe-12-0356
发表时间：
2013-01
期刊：
The Journal of endocrinology
影响因子：
--
作者：
Hinder LM;Vivekanandan-Giri A;McLean LL;Pennathur S;Feldman EL
通讯作者：
Feldman EL
影响因子：
5.3
作者：
Chen, S;Velardez, MO;Corfas, G
通讯作者：
Corfas, G
影响因子：
4.8
作者：
Huang, YZ;Zang, MW;Mei, L
通讯作者：
Mei, L