Dimethylfumarate attenuates renal fibrosis via NF-E2-related factor 2-mediated inhibition of transforming growth factor-β/Smad signaling.
Dimethylfumarate attenuates renal fibrosis via NF-E2-related factor 2-mediated inhibition of transforming growth factor-β/Smad signaling.
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DOI：
10.1371/journal.pone.0045870
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Lee IK
中科院分区：
文献类型：
--
作者：
Oh CJ;Kim JY;Choi YK;Kim HJ;Jeong JY;Bae KH;Park KG;Lee IK
TGF-β在肾纤维化的发生发展中起关键作用。抑制TGF-β信号传导途径是预防这种疾病的可能治疗方法，并且报告表明Nrf 2通过抑制TGF-β信号传导来防止肾纤维化。本研究检查了刺激Nrf 2的富马酸二甲酯（DMF）是否通过Nrf 2介导的TGF-β信号转导抑制来预防肾纤维化。结果显示，DMF可增加TGF-β诱导的大鼠系膜细胞（RMCs）和肾成纤维细胞（NRK-49 F）核内Nrf 2的表达，DMF和腺病毒介导的Nrf 2过表达（Ad-Nrf 2）均能降低派-1、α-平滑肌肌动蛋白（α-SMA）、纤连蛋白和1型胶原的表达。此外，DMF和Ad-Nrf 2通过抑制Smad 3磷酸化来抑制TGF-β刺激的Smad 3活性，而Smad 3磷酸化通过siRNA介导的Nrf 2表达敲低来恢复。然而，抗氧化反应元件（ARE）驱动的Nrf 2靶基因（如NQO 1、HO-1和谷胱甘肽S-转移酶（GST））的下调并未逆转DMF对TGF-β诱导的促纤维化基因或细胞外基质蛋白上调的抑制作用，表明DMF具有ARE非依赖性抗纤维化活性。最后，DMF抑制单侧输尿管梗阻（UUO）诱导的肾纤维化以及UUO小鼠梗阻肾中α-SMA、纤连蛋白和1型胶原蛋白的表达，沿着Nrf 2和磷酸化Smad 3的表达分别增加和减少。总之，DMF以ARE非依赖性方式通过Nrf 2介导的TGF-β/Smad 3信号转导抑制来减轻肾纤维化，表明DMF可用于治疗肾纤维化。
TGF-β plays a key role in the development of renal fibrosis. Suppressing the TGF-β signaling pathway is a possible therapeutic approach for preventing this disease, and reports have suggested that Nrf2 protects against renal fibrosis by inhibiting TGF-β signaling. This study examines whether dimethylfumarate (DMF), which stimulates Nrf2, prevents renal fibrosis via the Nrf2-mediated suppression of TGF-β signaling. Results showed that DMF increased nuclear levels of Nrf2, and both DMF and adenovirus-mediated overexpression of Nrf2 (Ad-Nrf2) decreased PAI-1, alpha-smooth muscle actin (α-SMA), fibronectin and type 1 collagen expression in TGF-β-treated rat mesangial cells (RMCs) and renal fibroblast cells (NRK-49F). Additionally, DMF and Ad-Nrf2 repressed TGF-β-stimulated Smad3 activity by inhibiting Smad3 phosphorylation, which was restored by siRNA-mediated knockdown of Nrf2 expression. However, downregulation of the antioxidant response element (ARE)-driven Nrf2 target genes such as NQO1, HO-1 and glutathione S-transferase (GST) did not reverse the inhibitory effect of DMF on TGF-β-induced upregulation of profibrotic genes or extracellular matrix proteins, suggesting an ARE-independent anti-fibrotic activity of DMF. Finally, DMF suppressed unilateral ureteral obstruction (UUO)-induced renal fibrosis and α-SMA, fibronectin and type 1 collagen expression in the obstructed kidneys from UUO mice, along with increased and decreased expression of Nrf2 and phospho-Smad3, respectively. In summary, DMF attenuated renal fibrosis via the Nrf2-mediated inhibition of TGF-β/Smad3 signaling in an ARE-independent manner, suggesting that DMF could be used to treat renal fibrosis.
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影响因子：
4.7
作者：
Lin SX;Lisi L;Dello Russo C;Polak PE;Sharp A;Weinberg G;Kalinin S;Feinstein DL
通讯作者：
Feinstein DL
DOI：
10.1097/01.asn.0000077411.98742.54
发表时间：
2003-08-01
影响因子：
13.6
作者：
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通讯作者：
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作者：
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影响因子：
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作者：
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影响因子：
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作者：
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