1Department of Medicine, University of Hong Kong, Hong Kong SAR, China.
Am J Physiol Renal Physiol. 2010 Apr;298(4):F1006-17. doi: 10.1152/ajprenal.00675.2009. Epub 2010 Jan 20.
Aristolochic acid nephropathy (AAN) has become a worldwide disease and is the most severe complication related to the use of traditional Chinese medicine. However, the pathogenic mechanisms of AAN remain unclear and therapies are limited. The present study tested the hypothesis that transforming growth factor (TGF)-beta/Smad3 may be a key pathway leading to chronic AAN. This was examined in vivo in Smad3 wild-type/knockout (WT/KO) mice and in vitro in tubular epithelial cells with knockdown of Smad2 or Smad3. Results revealed that chronic administration of aristolochic acid (AA) resulted in a severe AAN characterized by progressive renal dysfunction and tubulointerstitial fibrosis including epithelial-mesenchymal transition (EMT) in Smad3 WT mice, but not in Smad3 KO mice, suggesting a critical role for Smad3 in the development of AAN. This was further tested in vitro. We found that AA was able to activate Smad signaling to mediate EMT and renal fibrosis via both TGF-beta-dependent and JNK/MAP kinase-dependent mechanisms because blockade of JNK and specific knockdown of Smad3, but not Smad2, were able to attenuate AA-stimulated collagen matrix expression and EMT. In conclusion, TGF-beta/Smad3 may be an essential mediator for chronic AAN. Results from this study indicate that specific blockade of the TGF-beta/Smad3 signaling pathway may have therapeutic potential for chronic AAN.
马兜铃酸肾病（AAN）已成为一种全球性疾病，是与使用传统中药相关的最严重的并发症。然而，AAN 的发病机制仍不清楚，且治疗方法有限。本研究检验了这样一个假设，即转化生长因子（TGF）-β/Smad3 可能是导致慢性 AAN 的关键途径。这在 Smad3 野生型/敲除（WT/KO）小鼠体内和 Smad2 或 Smad3 敲低的肾小管上皮细胞中进行了体外研究。结果表明，慢性给予马兜铃酸（AA）可导致 Smad3 WT 小鼠发生严重的 AAN，其特征为进行性肾功能障碍和肾小管间质纤维化，包括上皮-间充质转化（EMT），但在 Smad3 KO 小鼠中则不会，这表明 Smad3 在 AAN 的发生发展中起关键作用。这在体外进一步得到了验证。我们发现，AA 能够通过 TGF-β 依赖和 JNK/MAP 激酶依赖机制激活 Smad 信号转导，介导 EMT 和肾纤维化，因为阻断 JNK 和特异性敲低 Smad3（而不是 Smad2）可减轻 AA 刺激的胶原基质表达和 EMT。总之，TGF-β/Smad3 可能是慢性 AAN 的重要介质。本研究结果表明，特异性阻断 TGF-β/Smad3 信号通路可能对慢性 AAN 具有治疗潜力。
