Peptide-based inhibition of IκB kinase/nuclear factor-κB pathway protects against diabetes-associated nephropathy and atherosclerosis in a mouse model of type 1 diabetes
Peptide-based inhibition of IκB kinase/nuclear factor-κB pathway protects against diabetes-associated nephropathy and atherosclerosis in a mouse model of type 1 diabetes
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DOI：
10.1007/s00125-015-3596-6
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发表时间：
2015-07-01
期刊：
影响因子：
8.2
通讯作者：
Gomez-Guerrero, Carmen
中科院分区：
文献类型：
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作者：
Oguiza, Ainhoa;Recio, Carlota;Gomez-Guerrero, Carmen
目的/假设经典核因子-κ B（NF-κ B）通路由NF-κ B激酶抑制剂（IKK）介导，调节参与糖尿病发病的炎症基因的转录，从早期到进展和最终并发症。IKK α/β中所含的NF-κ B必需调节剂结合结构域（NBD）对于IKK复合物组装是必需的。因此，我们研究了针对IKK依赖的NF-κ B通路在糖尿病相关肾病和动脉粥样硬化的进展的功能后果。方法载脂蛋白E缺陷型糖尿病小鼠链脲佐菌素诱导的IKK α/β NBD区域衍生的细胞渗透性肽进行治疗。分析肾脏和主动脉的形态学、白细胞浸润、胶原蛋白、NF-κ B活性和基因表达。在体外研究中进行了肾和血管cells.Results NBD肽管理不影响糖尿病的代谢严重程度，但导致肾保护，证明剂量依赖性减少蛋白尿，肾脏病变（系膜扩张，白细胞浸润和纤维化），核内NF-κ B活性和促炎症和促纤维化基因表达。此外，肽治疗通过降低脂质、白细胞和细胞因子的含量并增加斑块稳定性标记物来限制糖尿病小鼠中的动脉粥样硬化斑块形成。这种肾保护和抗动脉粥样硬化作用伴随着全身性T辅助细胞1细胞因子的下降。在体外，NBD肽可阻止IKK组装/激活、p65核转位、NF-κ B调节的基因表达以及高糖或炎症刺激诱导的细胞增殖。结论/解释基于肽的IKK复合物形成抑制可减弱NF-κ B的激活，抑制炎症并延缓糖尿病小鼠肾脏和血管损伤的进展。B从而为防治糖尿病炎症并发症提供了一种可行的途径。
Aims/hypothesis The canonical nuclear factor-kappa B (NF-kappa B) pathway mediated by the inhibitor of NF-kappa B kinase (IKK) regulates the transcription of inflammatory genes involved in the pathogenesis of diabetes, from the early phase to progression and final complications. The NF-kappa B essential modulator binding domain (NBD) contained in IKK alpha/beta is essential for IKK complex assembly. We therefore investigated the functional consequences of targeting the IKK-dependent NF-kappa B pathway in the progression of diabetes-associated nephropathy and atherosclerosis.Methods Apolipoprotein E-deficient mice with diabetes induced by streptozotocin were treated with a cell-permeable peptide derived from the IKK alpha/beta NBD region. Kidneys and aorta were analysed for morphology, leucocyte infiltrate, collagen, NF-kappa B activity and gene expression. In vitro studies were performed in renal and vascular cells.Results NBD peptide administration did not affect the metabolic severity of diabetes but resulted in renal protection, as evidenced by dose-dependent decreases in albuminuria, renal lesions (mesangial expansion, leucocyte infiltration and fibrosis), intranuclear NF-kappa B activity and proinflammatory and pro-fibrotic gene expression. Furthermore, peptide treatment limited atheroma plaque formation in diabetic mice by decreasing the content of lipids, leucocytes and cytokines and increasing plaque stability markers. This nephroprotective and anti-atherosclerotic effect was accompanied by a decline in systemic T helper 1 cytokines. In vitro, NBD peptide prevented IKK assembly/activation, p65 nuclear translocation, NF-kappa B-regulated gene expression and cell proliferation induced by either high glucose or inflammatory stimulation.Conclusions/interpretation Peptide-based inhibition of IKK complex formation attenuates NF-kappa B activation, suppresses inflammation and retards the progression of renal and vascular injury in diabetic mice, thus providing a feasible approach against diabetes inflammatory complications.