Smad7 suppresses renal fibrosis via altering expression of TGF-β/Smad3-regulated microRNAs
Smad7 suppresses renal fibrosis via altering expression of TGF-β/Smad3-regulated microRNAs
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DOI：
10.1038/mt.2012.251
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发表时间：
2013-02-01
影响因子：
12.4
通讯作者：
Lan, Hui Y.
中科院分区：
文献类型：
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作者：
Chung, Arthur C. K.;Dong, Yuan;Lan, Hui Y.
已知通过 Smad7 基因治疗阻断转化生长因子-β (TGF-β) 信号传导可预防实验性肾纤维化。本研究调查了 Smad7 是否通过改变肾纤维化相关 microRNA 的表达来抑制肾纤维化。通过过表达 Smad7 对梗阻性肾病患病肾脏和肾细胞进行基因治疗，可恢复 miR-29b，但抑制 miR-192 和 miR-21 的表达，从而阻断肾纤维化。此外，Smad7 过表达还抑制了这些 microRNA 的高级糖化终产物和血管紧张素 II 调节的表达。相反，破坏小鼠中的 Smad7 基因则显示出相反的结果，即增强 miR-29b 的丢失以及 miR-192 和 miR-21 的上调，从而促进梗阻性肾病模型的结扎肾脏中的肾纤维化。更重要的是，在过表达 Smad7 的肾小管上皮细胞中使用抗 miR-29b、miR-21 和 miR-192 模拟物治疗消除了 Smad7 对肾纤维化的抑制功能，表明这些 microRNA 在 Smad7 下游发挥作用，超越了 Smad7 功能。总之，Smad7 通过调节 TGF-β/Smad3 介导的 miR-21、miR-192 和 miR-29b 的肾脏表达来保护肾脏免受纤维化。恢复肾脏 miR-29b 但抑制 miR-192 和 miR-21 可能是 Smad7 基因治疗抑制肾纤维化的机制。
Blockade of transforming growth factor-beta (TGF-beta) signaling by Smad7 gene therapy is known to prevent experimental renal fibrosis. This study investigated whether Smad7 suppresses renal fibrosis via altering the renal expression of fibrosis-related microRNAs. Application of gene therapy into diseased kidneys of obstructive nephropathy and kidney cells by overexpressing Smad7 restored miR-29b but inhibited the expression of miR-192 and miR-21, resulting in blockade of renal fibrosis. Furthermore, Smad7 overexpression also suppressed advanced glycated end products- and angiotensin II-regulated expression of these microRNAs. In contrast, disruption of Smad7 gene in mice demonstrated opposite results by enhancing the loss of miR-29b and upregulation of miR-192 and miR-21, resulting in promotion of renal fibrosis in ligated kidneys of a model of obstructive nephropathy. More importantly, treatment with anti-miR-29b, miR-21 and miR-192 mimics in Smad7 overexpressing tubular epithelial cells abrogated the suppressive function of Smad7 on renal fibrosis, suggesting that these microRNAs act downstream of Smad7 to override the Smad7 function. In conclusion, Smad7 protects kidneys from fibrosis by regulating TGF-beta/Smad3-mediated renal expression of miR-21, miR-192, and miR-29b. Restored renal miR-29b but suppressed miR-192 and miR-21 may be a mechanism by which gene therapy with Smad7 inhibits renal fibrosis.