Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
PLoS One. 2013 Jun 14;8(6):e65549. doi: 10.1371/journal.pone.0065549. Print 2013.
Growth differentiation factor 15 (GDF15), a direct target gene of p53, is a multifunctional member of the TGF-β/BMP superfamily. GDF15 can be induced and is implicated as a key secretory cytokine in response to multiple cellular stimuli. Accumulating evidence indicates that GDF15 is associated with the development and prognosis of diabetes mellitus, while whether GDF15 can be induced by high glucose is unknown. In the present study, we revealed that high glucose could induce GDF15 expression and secretion in cultured human umbilical vein endothelial cells in a ROS- and p53-dependent manner. Inhibition of high glucose-induced GDF15 expression by siRNA demonstrated that adaptively induced GDF15 played a protective role against high glucose-induced human umbilical vein endothelial cell apoptosis via maintaining the active state of PI3K/Akt/eNOS pathway and attenuating NF-κB/JNK pathway activation. The protective effects of GDF15 were probably achieved by inhibiting ROS overproduction in high glucose-treated human umbilical vein endothelial cells in a negative feedback manner. Our results suggest that high glucose can promote GDF15 expression and secretion in human umbilical vein endothelial cells, which in turn attenuates high glucose-induced endothelial cell apoptosis.
生长分化因子 15（GDF15）是 p53 的直接靶基因，是 TGF-β/BMP 超家族的多功能成员。GDF15 可被诱导，并被认为是对多种细胞刺激的关键分泌细胞因子。越来越多的证据表明，GDF15 与糖尿病的发生和预后有关，而高葡萄糖是否能诱导 GDF15 的产生尚不清楚。在本研究中，我们揭示了高葡萄糖以 ROS 和 p53 依赖的方式诱导培养的人脐静脉内皮细胞中 GDF15 的表达和分泌。siRNA 抑制高葡萄糖诱导的 GDF15 表达表明，适应性诱导的 GDF15 通过维持 PI3K/Akt/eNOS 通路的激活状态和减轻 NF-κB/JNK 通路的激活，在高葡萄糖诱导的人脐静脉内皮细胞凋亡中发挥保护作用。GDF15 的保护作用可能是通过负反馈抑制高葡萄糖处理的人脐静脉内皮细胞中 ROS 的过度产生来实现的。我们的结果表明，高葡萄糖可以促进人脐静脉内皮细胞中 GDF15 的表达和分泌，进而减轻高葡萄糖诱导的内皮细胞凋亡。
