Stromal cell-derived factor-1 (SDF-1)/CXCL12 attenuates diabetes in mice and promotes pancreatic β-cell survival by activation of the prosurvival kinase Akt
Stromal cell-derived factor-1 (SDF-1)/CXCL12 attenuates diabetes in mice and promotes pancreatic β-cell survival by activation of the prosurvival kinase Akt
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DOI：
10.2337/db07-0291
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发表时间：
2007-12-01
期刊：
影响因子：
7.7
通讯作者：
Habener, Joel F.
中科院分区：
文献类型：
--
作者：
Yano, Tatsuya;Liu, Zhengyu;Habener, Joel F.
目的：糖尿病是由分泌胰岛素的胰岛β细胞缺乏引起的。通过增加增殖和存活来增加β细胞质量的方法是可取的。研究设计与方法：检测基质细胞衍生因子L/CXCL12及其受体CX趋化因子受体4在小鼠胰腺和克隆P细胞中的表达，SDF-1对AKT及其下游信号通路的激活，以及对链脲佐菌素诱导的细胞凋亡和糖尿病的保护作用。结果-CXCR4表达于β细胞，SDF-1表达于胰岛内微血管内皮细胞和周围间质组织。在其β细胞中过度表达SDF-1的转基因小鼠(RIP-SDF-1小鼠)对STZ诱导的β细胞凋亡和糖尿病具有抵抗力。在MIN6β细胞中，CXCR4拮抗剂(AMD3100)诱导细胞凋亡，增加活性氧，降低抗凋亡蛋白Bcl2的表达水平，并减少促凋亡蛋白Bad的磷酸化。在用SDF-1处理的INS-1细胞和AMD3100敏感的RIP-SDF-1小鼠的P细胞中，活性磷酸化生存期激酶Akt均增加。小干扰RNA抑制AKT的表达可减弱SDF-1对thapsigargin或葡萄糖剥夺诱导的INS-1P-细胞caspase依赖性凋亡的改善作用。结论SDF-1通过激活Akt促进胰岛β细胞存活，提示SDF-1激动剂对糖尿病的治疗可能是有益的。
OBJECTIVE-Diabetes is caused by a deficiency of pancreatic beta-cells that produce insulin. Approaches to enhance beta-cell mass by increasing proliferation and survival are desirable. We determined whether stromal cell-derived factor (SDF)-l/CXCL12 and its receptor, CX chemokine receptor (CXCR)4, are important for the survival of beta-cells.RESEARCH DESIGN AND METHODS-Mouse pancreata and clonal P-cells were examined for expression of SDF-1 and CXCR4, activation of AKT and downstream signaling pathways by SDF-1, and protection against apoptosis and diabetes induced by streptozotocin (STZ).RESULTS-CXCR4 is expressed in beta-cells, and SDF-1 is expressed in microvascular endothelial cells within the islets and in surrounding interstitial stromal tissue. Transgenic mice overexpressing SDF-1 within their beta-cells (RIP-SDF-1 mice) are resistant to STZ-induced beta-cell apoptosis and diabetes. In MIN6 beta-cells, a CXCR4 antagonist (AMD3100) induces apoptosis, increases reactive oxygen species, decreases expression levels of the anti-apoptotic protein Bcl-2, and reduces phosphorylation the proapoptotic protein Bad. Active phosphorylated prosurvival kinase Akt is increased both in the P-cells of RIP-SDF-1 mice in INS-1 cells treated with SDF-1 and sensitive to AMD3100. Inhibition of AKT expression by small interfering RNA attenuates the ameliorative effects of SDF-1 on caspase-dependent apoptosis induced by thapsigargin or glucose deprivation in INS-1 P-cells. Specific inhibition of Akt activation by a soluble inhibitor (SH-5) reverses the anti-apoptotic effects of SDF-1 in INS-1 cells and mouse islets.CONCLUSIONS-SDF-1 promotes pancreatic beta-cell survival via activation of Akt, suggesting that SDF-1 agonists may prove beneficial for treatment of diabetes.