Oguiza Ainhoa, Recio Carlota, Lazaro Iolanda, Mallavia Beñat, Blanco Julia, Egido Jesus, Gomez-Guerrero Carmen
Renal and Vascular Inflammation Group, IIS-Fundacion Jimenez Diaz, Autonoma University of Madrid, Avda. Reyes Catolicos, 2, 28040, Madrid, Spain.
Diabetologia. 2015 Jul;58(7):1656-67. doi: 10.1007/s00125-015-3596-6. Epub 2015 Apr 28.
AIMS/HYPOTHESIS: The canonical nuclear factor-κB (NF-κB) pathway mediated by the inhibitor of NF-κB 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-κB essential modulator binding domain (NBD) contained in IKKα/β is essential for IKK complex assembly. We therefore investigated the functional consequences of targeting the IKK-dependent NF-κB pathway in the progression of diabetes-associated nephropathy and atherosclerosis.
Apolipoprotein E-deficient mice with diabetes induced by streptozotocin were treated with a cell-permeable peptide derived from the IKKα/β NBD region. Kidneys and aorta were analysed for morphology, leucocyte infiltrate, collagen, NF-κB activity and gene expression. In vitro studies were performed in renal and vascular cells.
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-κB 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-κB-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-κB activation, suppresses inflammation and retards the progression of renal and vascular injury in diabetic mice, thus providing a feasible approach against diabetes inflammatory complications.
目的/假设：由核因子κB激酶（IKK）介导的经典核因子κB（NF-κB）信号通路调控着参与糖尿病发病机制的炎症基因转录，从疾病早期到进展期以及最终并发症阶段均发挥作用。IKKα/β中含有的NF-κB必需调节子结合域（NBD）对于IKK复合物的组装至关重要。因此，我们研究了靶向IKK依赖的NF-κB信号通路在糖尿病相关性肾病和动脉粥样硬化进展中的功能后果。
用链脲佐菌素诱导糖尿病的载脂蛋白E缺陷小鼠接受源自IKKα/β NBD区域的细胞穿透肽治疗。对肾脏和主动脉进行形态学、白细胞浸润、胶原蛋白、NF-κB活性及基因表达分析。在肾细胞和血管细胞中进行体外研究。
给予NBD肽不影响糖尿病的代谢严重程度，但具有肾脏保护作用，表现为蛋白尿、肾脏病变（系膜扩张、白细胞浸润和纤维化）、核内NF-κB活性以及促炎和促纤维化基因表达呈剂量依赖性降低。此外，肽治疗通过降低脂质、白细胞和细胞因子含量并增加斑块稳定性标志物，限制了糖尿病小鼠动脉粥样斑块的形成。这种肾脏保护和抗动脉粥样硬化作用伴随着全身辅助性T细胞1细胞因子水平的下降。在体外，NBD肽可阻止IKK组装/激活、p65核转位、NF-κB调控的基因表达以及高糖或炎症刺激诱导的细胞增殖。
结论/解读：基于肽的IKK复合物形成抑制可减弱NF-κB激活，抑制炎症并延缓糖尿病小鼠肾脏和血管损伤的进展，从而为对抗糖尿病炎症并发症提供了一种可行的方法。
