Silencing SMOC2 ameliorates kidney fibrosis by inhibiting fibroblast to myofibroblast transformation
Silencing SMOC2 ameliorates kidney fibrosis by inhibiting fibroblast to myofibroblast transformation
复制标题
DOI：
10.1172/jci.insight.90299
复制
发表时间：
2017-04-20
期刊：
影响因子：
8
通讯作者：
Vaidya, Vishal S.
中科院分区：
文献类型：
--
作者：
Gerarduzzi, Casimiro;Kumar, Ramya K.;Vaidya, Vishal S.
分泌型模块化钙结合蛋白2（SMOC 2）属于分泌型蛋白质家族，其成员是调节细胞-基质相互作用的酸性和富含半胱氨酸的蛋白质。我们报告说，SMOC 2在小鼠和人类的肾小管上皮细胞纤维化后上调。我们使用SMOC 2过表达或敲低的基因操作小鼠，表明SMOC 2在肾脏纤维化的进展中发挥着关键作用。从机制上讲，我们发现SMOC 2激活成纤维细胞到肌成纤维细胞的转变（FMT），以刺激应力纤维的形成，增殖，迁移和细胞外基质的产生。此外，我们证明，通过siRNA靶向SMOC 2导致体外TGFa 1介导的FMT的衰减和小鼠肾纤维化的改善。这些发现表明，SMOC 2是受损肾脏病理分泌组中的关键信号分子，靶向SMOC 2提供了抑制FMT介导的肾脏纤维化的治疗策略-这是一种未满足的医疗需求。
Secreted modular calcium-binding protein 2 (SMOC2) belongs to the secreted protein acidic and rich in cysteine (SPARC) family of matricellular proteins whose members are known to modulate cell-matrix interactions. We report that SMOC2 is upregulated in the kidney tubular epithelial cells of mice and humans following fibrosis. Using genetically manipulated mice with SMOC2 overexpression or knockdown, we show that SMOC2 is critically involved in the progression of kidney fibrosis. Mechanistically, we found that SMOC2 activates a fibroblast-to-myofibroblast transition (FMT) to stimulate stress fiber formation, proliferation, migration, and extracellular matrix production. Furthermore, we demonstrate that targeting SMOC2 by siRNA results in attenuation of TGFa1-mediated FMT in vitro and an amelioration of kidney fibrosis in mice. These findings implicate that SMOC2 is a key signaling molecule in the pathological secretome of a damaged kidney and targeting SMOC2 offers a therapeutic strategy for inhibiting FMT-mediated kidney fibrosis - an unmet medical need.