Treatment of renal fibrosis by rebalancing TGF-β/Smad signaling with the combination of asiatic acid and naringenin.
Treatment of renal fibrosis by rebalancing TGF-β/Smad signaling with the combination of asiatic acid and naringenin.
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DOI：
10.18632/oncotarget.6100
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发表时间：
2015-11-10
期刊：
影响因子：
--
通讯作者：
Lan HY
中科院分区：
文献类型：
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作者：
Meng XM;Zhang Y;Huang XR;Ren GL;Li J;Lan HY
我们最近表明，TGF -β/Smad信号通路失衡，Smad3过度激活而Smad7水平较低，是组织纤维化的核心机制。在本研究中，我们在此报告，柚皮素（NG）对Smad3的抑制以及积雪草酸（AA）对Smad7的上调，在梗阻性肾病小鼠模型中对肾纤维化的抑制产生了协同作用。我们发现，AA是一种来自积雪草的三萜类化合物，作为Smad7激动剂发挥作用，通过诱导Smad7抑制TGF -β/Smad3介导的肾纤维化。而NG是一种来自葡萄柚和柑橘类水果的黄酮类化合物，是一种Smad3抑制剂，通过阻断Smad3的磷酸化和转录来抑制肾纤维化。AA和NG的组合通过阻断Smad3同时上调Smad7，对肾纤维化的抑制产生了协同作用。因此，通过AA和NG治疗来重新平衡TGF -β/Smad信号通路的紊乱，可能代表一种针对与纤维化相关的慢性肾脏病的新型有效疗法。
We recently showed that imbalance of TGF-β/Smad signaling with over-activation of Smad3 but lower levels of Smad7 is a central mechanism of tissue fibrosis. In the present study, we report here that inhibition of Smad3 with naringenin (NG) and upregulation of Smad7 with asiatic acid (AA) produced an additive effect on inhibition of renal fibrosis in a mouse model of obstructive nephropathy. We found that AA, a triterpene from Centella Asiatica, functioned as a Smad7 agonist and suppressed TGF-β/Smad3-mediated renal fibrosis by inducing Smad7. Whereas, NG, a flavonoid from grapefruits and citrus fruits, was a Smad3 inhibitor that inhibited renal fibrosis by blocking Smad3 phosphorylation and transcription. The combination of AA and NG produced an additive effect on inhibition of renal fibrosis by blocking Smad3 while upregulating Smad7. Thus, rebalancing the disorder of TGF-β/Smad signaling by treatment with AA and NG may represent as a novel and effective therapy for chronic kidney disease associated with fibrosis.