Conditional Deletion of Smad1 Ameliorates Glomerular Injury in Progressive Glomerulonephritis.
Conditional Deletion of Smad1 Ameliorates Glomerular Injury in Progressive Glomerulonephritis.
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DOI：
10.1038/srep31216
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发表时间：
2016-08-05
影响因子：
4.6
通讯作者：
Doi T
中科院分区：
文献类型：
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作者：
Araki M;Matsubara T;Abe H;Torikoshi K;Mima A;Iehara N;Fukatsu A;Kita T;Arai H;Doi T
在各种肾小球损伤中可观察到基质扩张和细胞增殖。然而，导致这些变化的分子机制尚未完全阐明。我们已经报道Smad1是一个关键的信号分子，在系膜基质扩张中调节IV型胶原（Col4）的转录，从而参与急性肾小球肾炎模型的肾小球损伤。在这项研究中，我们通过在Rosa26CreERT2小鼠（Smad1- cko）中条件缺失Smad1，研究了Smad1信号在加速肾毒性肾炎（NTN）中的作用，NTN是一种进行性肾小球肾炎模型。与野生型小鼠相比，添加NTN的Smad1-CKO小鼠系膜基质扩张明显受到抑制，这与Col4表达水平的降低是一致的。另一方面，在NTN模型中，STAT3激活和细胞增殖不受Smad1缺失的影响。因此，我们研究了在缺乏Smad1的情况下激活细胞增殖的另一个因素。在小鼠系膜细胞中，Id2诱导VEGF分泌并随后激活STAT3，独立于Smad1的表达。在进展性肾小球肾炎中，Smad1在肾小球损伤的发展中发挥重要作用，而不影响细胞增殖。
Matrix expansion and cell proliferation are concomitantly observed in various glomerular injuries. However, the molecular mechanisms responsible for these changes have not been fully elucidated. We have reported that Smad1 is a key signalling molecule that regulates the transcription of type IV collagen (Col4) in mesangial matrix expansion and is thereby involved in glomerular injury in an acute model of glomerulonephritis. In this study, we addressed the role of Smad1 signalling in accelerated nephrotoxic nephritis (NTN), a model of progressive glomerulonephritis, using conditional deletion of Smad1 in Rosa26CreERT2 mice (Smad1-CKO). Mesangial matrix expansion in the Smad1-CKO mice with NTN was significantly inhibited compared with that in wild type mice with NTN, which was consistent with the decrease in Col4 expression level. On the other hand, STAT3 activation and cell proliferation were not influenced by Smad1 deletion in the NTN model. Therefore, we investigated another factor that activates cell proliferation in the absence of Smad1. Id2 induced VEGF secretion and subsequent STAT3 activation, independently of Smad1 expression in mouse mesangial cells. Here we show that Smad1 plays an important role in the development of glomerular injury without affecting cell proliferation, in progressive glomerulonephritis.