Scleraxis Modulates Bone Morphogenetic Protein 4 (BMP4)-Smad1 Protein-Smooth Muscle α-Actin (SMA) Signal Transduction in Diabetic Nephropathy
Scleraxis Modulates Bone Morphogenetic Protein 4 (BMP4)-Smad1 Protein-Smooth Muscle α-Actin (SMA) Signal Transduction in Diabetic Nephropathy
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DOI：
10.1074/jbc.m111.275610
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发表时间：
2012-06-08
影响因子：
4.8
通讯作者：
Doi, Toshio
中科院分区：
文献类型：
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作者：
Abe, Hideharu;Tominaga, Tatsuya;Doi, Toshio
系膜细胞 (MC) 的激活，其特征是诱导平滑肌 α-肌动蛋白 (SMA) 表达，是各种肾脏疾病的关键事件；然而，控制 MC 分化的机制仍然很大程度上不明确。激活的 Smad1 在 MC 中以剂量依赖性方式诱导 SMA。作为 SMA 的直接调节分子，我们鉴定并表征了 scleraxis (Scx) 作为晚期糖基化终产物 (AGE) 暴露的 MC 中的一种新表型调节剂。 Scx 与 E12 物理相关，并结合 SMA 启动子中的 E-box，负向调节 AGE 诱导的 SMA 表达。 Scx 诱导骨形态发生蛋白 4 (BMP4) 的表达和分泌，从而控制 AGE 处理的 MC 中 Smad1 的激活。在糖尿病小鼠中，Scx 在肾小球中与 SMA 同时表达。通过 AGE 的长期处理进一步诱导分化抑制剂 1 (Id1)，从而将 Scx 从 SMA 启动子中移出。这些数据表明，除了TGFβ1-Smad1-SMA信号转导通路外，Scx和Id1还参与BMP4-Smad1-SMA信号转导通路，并调节糖尿病肾病中MC的表型变化。
Activation of mesangial cells (MCs), which is characterized by induction of smooth muscle alpha-actin (SMA) expression, contributes to a key event in various renal diseases; however, the mechanisms controlling MC differentiation are still largely undefined. Activated Smad1 induced SMA in a dose-dependent manner in MCs. As a direct regulating molecule for SMA, we identified and characterized scleraxis (Scx) as a new phenotype modulator in advanced glycation end product (AGE)-exposed MCs. Scx physically associated with E12 and bound the E-box in the promoter of SMA and negatively regulated the AGE-induced SMA expression. Scx induced expression and secretion of bone morphogenetic protein 4 (BMP4), thereby controlling the Smad1 activation in AGE-treated MCs. In diabetic mice, Scx was concomitantly expressed with SMA in the glomeruli. Inhibitor of differentiation 1 (Id1) was further induced by extended treatment with AGE, thereby dislodging Scx from the SMA promoter. These data suggest that Scx and Id1 are involved in the BMP4-Smad1-SMA signal transduction pathway besides the TGF beta 1-Smad1-SMA signaling pathway and modulate phenotypic changes in MCs in diabetic nephropathy.