Novel Interplay Between Smad1 and Smad3 Phosphorylation via AGE Regulates the Progression of Diabetic Nephropathy.
Novel Interplay Between Smad1 and Smad3 Phosphorylation via AGE Regulates the Progression of Diabetic Nephropathy.
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DOI：
10.1038/s41598-018-28439-1
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发表时间：
2018-07-12
影响因子：
4.6
通讯作者：
Doi T
中科院分区：
文献类型：
--
作者：
Ono H;Abe H;Sakurai A;Ochi A;Tominaga T;Tamaki M;Kishi S;Murakami T;Nagai K;Kohashi M;Doi T
糖尿病肾病（DN）是终末期肾功能衰竭的主要原因，与其他肾脏疾病原因相比，其发病率和死亡率增加。我们以前发现Smad 1在体外和体内DN的发展中起着关键作用。然而，Smad 1和Smad 3信号在DN中的功能相互作用尚不清楚。在这里，我们解决了Smad 1和Smad 3信号之间的分子相互作用在糖尿病条件下，通过使用Smad 3基因敲除糖尿病小鼠。在db/db小鼠的肾小球中观察到细胞外基质（ECM）蛋白过度表达和Smad 1活化，但在Smad 3 +/−; db/db小鼠的肾小球中受到抑制。在晚期糖基化终产物处理的系膜细胞（MC）中，Smad 3的激活增强了Smad 1 C端结构域的磷酸化，但降低了连接结构域的磷酸化，从而调节了Smad 1的激活。然而，Smad 1连接结构域的强制磷酸化并不影响MC中Smad 3的激活。Smad 3 +/−; db/db小鼠和普罗布考处理的db/db小鼠中Smad 1连接结构域的磷酸化增加，这与ECM过度产生的减弱一致。这些结果表明，Smad 3的表达和激活或普罗布考治疗改变了Smad 1的磷酸化，从而提出了新的分子机制，DN的发展和进展。
Diabetic nephropathy (DN) is the major cause of end-stage renal failure and is associated with increased morbidity and mortality compared with other causes of renal diseases. We previously found that Smad1 plays a critical role in the development of DN both in vitro and in vivo. However, functional interaction between Smad1 and Smad3 signaling in DN is unclear. Here, we addressed the molecular interplay between Smad1 and Smad3 signaling under a diabetic condition by using Smad3-knockout diabetic mice. Extracellular matrix (ECM) protein overexpression and Smad1 activation were observed in the glomeruli of db/db mice but were suppressed in the glomeruli of Smad3+/−; db/db mice. Smad3 activation enhanced the phosphorylation of Smad1 C-terminal domain but decreased the phosphorylation of linker domain, thus regulating Smad1 activation in advanced glycation end product-treated mesangial cells (MCs). However, forced phosphorylation of the Smad1 linker domain did not affect Smad3 activation in MCs. Phosphorylation of the Smad1 linker domain increased in Smad3+/−; db/db mice and probucol-treated db/db mice, which was consistent with the attenuation of ECM overproduction. These results indicate that Smad3 expression and activation or probucol treatment alters Smad1 phosphorylation, thus suggesting new molecular mechanisms underlying DN development and progression.
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影响因子：
4.8
作者：
Abe, H;Matsubara, T;Doi, T
通讯作者：
Doi, T
影响因子：
13.6
作者：
Kondo, Shuji;Shimizu, Maki;Kagami, Shoji
通讯作者：
Kagami, Shoji
影响因子：
5.1
作者：
Endo, K;Miyashita, Y;Shirai, K
通讯作者：
Shirai, K
影响因子：
3.7
作者：
Hirano T;Murakami T;Ono H;Sakurai A;Tominaga T;Takahashi T;Nagai K;Doi T;Abe H
通讯作者：
Abe H
影响因子：
4.6
作者：
Araki M;Matsubara T;Abe H;Torikoshi K;Mima A;Iehara N;Fukatsu A;Kita T;Arai H;Doi T
通讯作者：
Doi T