Transforming growth factor-β/Smad signalling in diabetic nephropathy
Transforming growth factor-β/Smad signalling in diabetic nephropathy
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DOI：
10.1111/j.1440-1681.2011.05663.x
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发表时间：
2012-08-01
影响因子：
2.9
通讯作者：
Lan, Hui Yao
中科院分区：
文献类型：
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作者：
Lan, Hui Yao
糖尿病肾病（Diabetic nephropathy， DN）是一种主要的糖尿病并发症，由转化生长因子(TGF)- β 1通过smad依赖性和非依赖性信号通路介导。在糖尿病条件下，许多促纤维化因子，如晚期糖基化终产物和血管紧张素II，也可以通过细胞外信号调节激酶/p38丝裂原活化蛋白激酶esmad信号通路激活Smad信号通路。因此，Smads作为信号集成商并与其他信号通路相互作用以介导DN。在肾纤维化的情况下，Smad3是致病的，但Smad2是保护性的。Smad3的缺失会抑制结缔组织生长因子和血管内皮生长因子的表达，而Smad2的破坏则会上调结缔组织生长因子和血管内皮生长因子的表达，并促进上皮-肌成纤维细胞和内皮-肌成纤维细胞的转化。Smad7在DN中起保护作用，因为Smad7的缺失会增强，而Smad7的过表达会抑制smad3介导的肾纤维化和核因子κ b驱动的肾炎症。转化生长因子- β 1激活Smad3调节介导肾纤维化的microrna。其中，miR-21和miR-192上调，而miR-29和miR-200家族下调。通过过表达与纤维化相关的Smad7-或smad3依赖性microRNA靶向下游tgf - β /Smad信号传导，可能是治疗DN的一种新颖有效的策略。
Diabetic nephropathy (DN) is a major diabetic complication that is mediated by transforming growth factor (TGF)-beta 1 via Smad-dependent and -independent signalling pathways. Under diabetic conditions, many profibrotic factors, such as advanced glycation end-products and angiotensin II, can also activate the Smad signalling pathway via the extracellular signal-regulated kinase/p38 mitogen-activated protein kinaseSmad signalling cross-talk pathway. Thus, Smads act as signal integrators and interact with other signalling pathways to mediate DN. In the context of renal fibrosis, Smad3 is pathogenic, but Smad2 is protective. Deletion of Smad3 inhibits, whereas disruption of Smad2 upregulates, connective tissue growth factor and vascular endothelial growth factor expression and promotes both epithelialmyofibroblast and endothelialmyofibroblast transition. Smad7 plays a protective role in DN because deletion of Smad7 enhances, whereas overexpression of Smad7 inhibits, Smad3-mediated renal fibrosis and nuclear factor-kappa B-driven renal inflammation. Transforming growth factor-beta 1 activates Smad3 to regulate microRNAs that mediate renal fibrosis. Of these, miR-21 and miR-192 are upregulated, whereas the miR-29 and miR-200 families are downregulated. Targeting downstream TGF-beta/Smad signalling by overexpressing Smad7- or Smad3-dependent microRNA related to fibrosis may represent a novel and effective strategy for the treatment of DN.