Disruption of hepatocyte growth factor/c-Met signaling enhances pancreatic beta-cell death and accelerates the onset of diabetes.
Disruption of hepatocyte growth factor/c-Met signaling enhances pancreatic beta-cell death and accelerates the onset of diabetes.
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DOI：
10.2337/db09-1305
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发表时间：
2011-02
期刊：
影响因子：
7.7
通讯作者：
Garcia-Ocaña A
中科院分区：
文献类型：
--
作者：
Mellado-Gil J;Rosa TC;Demirci C;Gonzalez-Pertusa JA;Velazquez-Garcia S;Ernst S;Valle S;Vasavada RC;Stewart AF;Alonso LC;Garcia-Ocaña A
确定肝细胞生长因子（HGF）/c-Met对体内致糖尿病条件下β细胞存活和体外细胞因子应答的作用。我们产生了胰腺特异性c-Met-null（PancMet KO）小鼠，并表征了它们对多次低剂量链脲佐菌素（MLDS）给药诱导的糖尿病的反应。我们还分析了体外HGF/c-Met信号传导对小鼠和人胰岛中精氨酸诱导的β细胞死亡的影响，特别是检查了核因子（NF）-κB的作用。体外暴露于细胞因子或来自MLDS处理的小鼠的胰岛显示出显著增加的HGF和c-Met水平，表明HGF/c-Met在β细胞存活中对抗致糖尿病剂的潜在作用。成年PancMet KO小鼠显示出正常的葡萄糖和β细胞稳态，表明胰腺c-Met丢失在基础条件下对β细胞生长和功能无害。然而，PancMet KO小鼠对MLDS诱导的糖尿病更易感。与野生型同窝仔相比，它们显示出更高的血糖水平、显著的低胰岛素血症和减少的β细胞质量。PancMet KO小鼠显示胰岛内浸润、胰岛一氧化氮（NO）和趋化因子产生以及β细胞凋亡增强。c-Met-null β-细胞在体外对苦参碱诱导的细胞死亡更敏感，这种效应由NF-κB激活和NO产生介导。相反，HGF处理降低了p65/NF-κB活化，并完全保护小鼠和更重要的人β细胞免受细胞因子的影响。这些结果表明，HGF/c-Met通过减弱NF-κB信号传导对β细胞存活至关重要，并表明HGF/c-Met信号传导途径的激活代表了增强β细胞保护的新策略。
To determine the role of hepatocyte growth factor (HGF)/c-Met on β-cell survival in diabetogenic conditions in vivo and in response to cytokines in vitro. We generated pancreas-specific c-Met-null (PancMet KO) mice and characterized their response to diabetes induced by multiple low-dose streptozotocin (MLDS) administration. We also analyzed the effect of HGF/c-Met signaling in vitro on cytokine-induced β-cell death in mouse and human islets, specifically examining the role of nuclear factor (NF)-κB. Islets exposed in vitro to cytokines or from MLDS-treated mice displayed significantly increased HGF and c-Met levels, suggesting a potential role for HGF/c-Met in β-cell survival against diabetogenic agents. Adult PancMet KO mice displayed normal glucose and β-cell homeostasis, indicating that pancreatic c-Met loss is not detrimental for β-cell growth and function under basal conditions. However, PancMet KO mice were more susceptible to MLDS-induced diabetes. They displayed higher blood glucose levels, marked hypoinsulinemia, and reduced β-cell mass compared with wild-type littermates. PancMet KO mice showed enhanced intraislet infiltration, islet nitric oxide (NO) and chemokine production, and β-cell apoptosis. c-Met-null β-cells were more sensitive to cytokine-induced cell death in vitro, an effect mediated by NF-κB activation and NO production. Conversely, HGF treatment decreased p65/NF-κB activation and fully protected mouse and, more important, human β-cells against cytokines. These results show that HGF/c-Met is critical for β-cell survival by attenuating NF-κB signaling and suggest that activation of the HGF/c-Met signaling pathway represents a novel strategy for enhancing β-cell protection.
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DOI：
10.1073/pnas.87.14.5238
发表时间：
1990-07-01
影响因子：
11.1
作者：
FARBER, JM
通讯作者：
FARBER, JM
影响因子：
4.8
作者：
Johansson, M;Mattsson, G;Carlsson, PO
通讯作者：
Carlsson, PO
影响因子：
4.8
作者：
Giannoukakis, N;Rudert, WA;Robbins, PD
通讯作者：
Robbins, PD
影响因子：
12.8
作者：
Grewal, IS;Grewal, KD;Flavell, RA
通讯作者：
Flavell, RA
DOI：
10.1073/pnas.90.5.1731
发表时间：
1993-03-01
影响因子：
11.1
作者：
CORBETT, JA;SWEETLAND, MA;MCDANIEL, ML
通讯作者：
MCDANIEL, ML