Diverse roles of TGF-β/Smads in renal fibrosis and inflammation.
Diverse roles of TGF-β/Smads in renal fibrosis and inflammation.
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DOI：
10.7150/ijbs.7.1056
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发表时间：
2011
影响因子：
9.2
通讯作者：
Lan HY
中科院分区：
文献类型：
--
作者：
Lan HY
长期以来，转化生长因子-β-1一直被认为是肾纤维化的关键介质，并在很大程度上通过激活其下游的Smad信号通路而导致肾脏瘢痕形成。有趣的是，当过度表达活性转化生长因子-β1的小鼠发生进行性肾脏损伤时，潜伏的转化生长因子-β1在肾脏纤维化和炎症中起到保护作用。在疾病条件下，Smad2和Smad3被高度激活，而Smad7通过泛素蛋白酶体降解机制被降解。除转化生长因子-β1外，许多致病介质如血管紧张素II和晚期糖基化终末产物也可通过转化生长因子-β依赖和独立的机制激活Smad通路。Smads与其他信号通路相互作用，如MAPK和NF-κB通路，积极或消极地调节肾脏炎症和纤维化。来自基因敲除小鼠的研究表明，转化生长因子-β1通过刺激其下游的Smad以不同的方式调节肾脏损伤而发挥作用。在肾脏纤维化和炎症的背景下，Smad3是致病的，而Smad2和Smad7是保护的。Smad4通过转录增强Smad3介导的肾脏纤维化，同时通过Smad7依赖的机制抑制NF-κB介导的肾炎症，发挥其不同的作用。此外，我们还证明了转化生长因子-β1通过刺激Smad3正向或负向调节microRNAs来发挥其在肾脏疾病中的纤维化作用。结论：转化生长因子-β/Smad信号通路是导致肾脏疾病的主要途径。Smad3是肾脏纤维化和炎症的关键介质，而Smad2和Smad7具有肾脏保护作用。Smad4在促进肾纤维化和抑制炎症方面发挥着不同的作用。因此，通过基因转移Smad7或Smad3依赖的microRNAs来靶向下游的转化生长因子-β/Smad3信号通路可能是一种特异而有效的肾脏疾病治疗策略。
TGF-β1 has been long considered as a key mediator in renal fibrosis and induces renal scarring largely by activating its downstream Smad signaling pathway. Interestingly, while mice overexpressing active TGF-β1 develop progressive renal injury, latent TGF-β1 plays a protective role in renal fibrosis and inflammation. Under disease conditions, Smad2 and Smad3 are highly activated, while Smad7 is degraded through the ubiquitin proteasome degradation mechanism. In addition to TGF-β1, many pathogenic mediators such as angiotensin II and advanced glycation end products can also activate the Smad pathway via both TGF-β-dependent and independent mechanisms. Smads interact with other signaling pathways, such as the MAPK and NF-κB pathways, to positively or negatively regulate renal inflammation and fibrosis. Studies from gene knockout mice demonstrate that TGF-β1 acts by stimulating its downstream Smads to diversely regulate kidney injury. In the context of renal fibrosis and inflammation, Smad3 is pathogenic, while Smad2 and Smad7 are protective. Smad4 exerts its diverse roles by transcriptionally enhancing Smad3-mediated renal fibrosis while inhibiting NF-κB-driven renal inflammation via a Smad7-dependent mechanism. Furthermore, we also demonstrated that TGF-β1 acts by stimulating Smad3 to positively or negatively regulate microRNAs to exert its fibrotic role in kidney disease. In conclusion, TGF-β/Smad signaling is a major pathway leading to kidney disease. Smad3 is a key mediator in renal fibrosis and inflammation, whereas Smad2 and Smad7 are renoprotective. Smad4 exerts its diverse role in promoting renal fibrosis while inhibiting inflammation. Thus, targeting the downstream TGF-β/Smad3 signaling pathway by gene transfer of either Smad7 or Smad3-dependent microRNAs may represent a specific and effective therapeutic strategy for kidney disease.
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