Overexpression of Circulating Soluble Nogo-B Improves Diabetic Kidney Disease by Protecting the Vasculature
Overexpression of Circulating Soluble Nogo-B Improves Diabetic Kidney Disease by Protecting the Vasculature
复制标题
循环中可溶性 Nogo-B 的过度表达通过保护脉管系统改善糖尿病肾病
DOI：
10.2337/db19-0157
复制
发表时间：
2019-09-01
期刊：
影响因子：
7.7
通讯作者：
Gnudi, Luigi
中科院分区：
文献类型：
--
作者：
Hernandez-Diaz, Ivan;Pan, Jiaqi;Gnudi, Luigi
血管损伤是导致慢性糖尿病微血管并发症的主要机制，如糖尿病肾病，表现为白蛋白尿。因此，保护糖尿病血管系统的治疗具有显着的治疗潜力。可溶性神经突生长因子-B（sNogo-B）是全长Nogo-B的循环N-末端同种型，其在损伤后的血管重塑中起关键作用。然而，目前没有关于sNogo-B在糖尿病肾病背景下的作用的信息。我们证明sNogo-B在循环中的过表达通过减少蛋白尿、超滤和异常血管生成以及保护肾小球毛细血管结构来改善糖尿病肾病。糖尿病小鼠中的系统性sNogo-B过表达也与抑制血管内皮生长因子-A信号传导和减少内皮一氧化氮合酶、AKT和GSK 3 β磷酸化有关。此外，sNogo-B防止了当人内皮细胞暴露于糖尿病肾病患者的血清时发生的管形成的损害。总的来说，这些研究提供了第一个证据表明sNogo-B保护糖尿病血管系统，并可能代表糖尿病血管并发症的新治疗靶点。
Damage to the vasculature is the primary mechanism driving chronic diabetic microvascular complications such as diabetic nephropathy, which manifests as albuminuria. Therefore, treatments that protect the diabetic vasculature have significant therapeutic potential. Soluble neurite outgrowth inhibitor-B (sNogo-B) is a circulating N-terminus isoform of full-length Nogo-B, which plays a key role in vascular remodeling following injury. However, there is currently no information on the role of sNogo-B in the context of diabetic nephropathy. We demonstrate that overexpression of sNogo-B in the circulation ameliorates diabetic kidney disease by reducing albuminuria, hyperfiltration, and abnormal angiogenesis and protecting glomerular capillary structure. Systemic sNogo-B overexpression in diabetic mice also associates with dampening vascular endothelial growth factor-A signaling and reducing endothelial nitric oxide synthase, AKT, and GSK3 beta phosphorylation. Furthermore, sNogo-B prevented the impairment of tube formation, which occurred when human endothelial cells were exposed to sera from patients with diabetic kidney disease. Collectively, these studies provide the first evidence that sNogo-B protects the vasculature in diabetes and may represent a novel therapeutic target for diabetic vascular complications.