Different roles for TGF-β and VEGF in the pathogenesis of the cardinal features of diabetic nephropathy
Different roles for TGF-β and VEGF in the pathogenesis of the cardinal features of diabetic nephropathy
复制标题
DOI：
10.1016/j.diabres.2008.09.016
复制
发表时间：
2008-11-13
影响因子：
5.1
通讯作者：
Ziyadeh, Fuad N.
中科院分区：
文献类型：
--
作者：
Ziyadeh, Fuad N.
血液动力学应激与高血糖、糖化蛋白和氧化应激激活的代谢途径协同作用，诱导肾脏中的许多生长因子。纤维化细胞因子转化生长因子-β（TGF-β）通过其Smad 3信号传导途径是糖尿病中肾肥大和系膜细胞外基质成分积聚的病原体。中和抗TGF-β抗体、反义TGF-1 β寡脱氧核苷酸或敲除Smad 3基因预防和/或逆转小鼠中糖尿病状态的肥大和促纤维化作用。然而，有有限的证据支持TGF-β在蛋白尿的发展中的作用。足细胞衍生的血管内皮生长因子（VEGF）是一种渗透性和血管生成因子，其表达在糖尿病肾病动物模型中也增加，似乎以一种新的自分泌信号传导模式诱导糖尿病足细胞病，特别是蛋白尿的发生。因此，未来糖尿病肾病的治疗策略可能需要涉及TGF-β和VEGF信号通路的拦截，以对抗基质积累并改善白蛋白尿。阻断肾素-血管紧张素系统可以达到这一目的，但需要开发其他更有效的新策略。然而，应注意不要将这两种信号通路的活性降低到远低于正常水平，因为每种信号通路的基础活性对于肾小球细胞的最佳稳态是必不可少的。(C)2008年由Elsevier爱尔兰有限公司出版。
Hemodynamic stress in concert with metabolic pathways that are activated by hyperglycemia, glycated proteins, and oxidative stress induce a host of growth factors in the kidney. The fibrogenic cytokine transforming growth factor-beta (TGF-beta), through its Smad3 signaling pathway, is the etiologic agent of renal hypertrophy and the accumulation of mesangial extracellular matrix components in diabetes. Neutralizing anti-TGF-beta antibodies, antisense TGF-1 beta oligo de oxynucleotides or knocking off the Smad3 gene prevent and/or reverse the hypertrophic and profibrotic effects of the diabetic state in mice. However, there is limited evidence to support a role for TGF-beta in the development of albuminuria. Podocyte-derived vascular endothelial growth factor (VEGF), a permeability and angiogenic factor whose expression is also increased in animal models of diabetic kidney disease, appears to act in a novel autocrine signaling mode to induce the podocytopathy of diabetes, especially the genesis of albuminuria. Future strategies for therapy of diabetic nephropathy may therefore need to involve interception of both the TGF-beta and the VEGF signaling pathways to counter the matrix accumulation and to improve the albuminuria. interception of the renin-angiotensin system may achieve this goal but other novel strategies will need to be developed that would be more efficacious. However, a note of caution should be raised not to lower the heightened activities of these two signaling pathways much below normal levels because a basal activity for each is essential for the optimal homeostasis of glomerular cells. (C) 2008 Published by Elsevier Ireland Ltd.