Upregulation of mitochondrial Nox4 mediates TGF-β-induced apoptosis in cultured mouse podocytes
Upregulation of mitochondrial Nox4 mediates TGF-β-induced apoptosis in cultured mouse podocytes
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DOI：
10.1152/ajprenal.00438.2013
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发表时间：
2014-01-01
影响因子：
4.2
通讯作者：
Park, Kyu-Sang
中科院分区：
文献类型：
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作者：
Das, Ranjan;Xu, Shanhua;Park, Kyu-Sang
足细胞的损伤导致以蛋白尿为特征的慢性肾脏疾病的发作。肾组织中转化生长因子（TGF）-β升高与足细胞损伤相关，最终导致细胞凋亡和脱落。我们研究了TGF-β在永生化小鼠足细胞中的促凋亡机制。外源性TGF-β 1通过激活caspase-3诱导足细胞凋亡，这与选择性上调NADPH氧化酶4（Nox 4）产生的ROS水平升高有关。在小鼠足细胞中，Nox 4主要定位于线粒体，TGF-β 1上调Nox 4可显著降低线粒体膜电位。TGF-β 1诱导的ROS产生和caspase激活可通过抗氧化剂、Nox抑制剂diphenyleneiodonium或Nox 4的小干扰RNA来减轻。TGF-β受体I阻滞剂SB-431542完全逆转了TGF-β引发的变化（1）。Smad2或Smad3的敲除阻止了Nox 4表达的增加、ROS的产生、线粒体膜电位的丧失以及TGF-β激活的caspase-3（1）。这些结果表明，TGF-β 1通过TGF-β受体-Smad2/3途径诱导的线粒体Nox 4上调是ROS产生、线粒体功能障碍和细胞凋亡的原因，这可能至少部分地导致蛋白尿性肾小球疾病如糖尿病肾病的发生和进展。
Injury to podocytes leads to the onset of chronic renal diseases characterized by proteinuria. Elevated transforming growth factor (TGF)-beta in kidney tissue is associated with podocyte damage that ultimately results in apoptosis and detachment. We investigated the proapoptotic mechanism of TGF-beta in immortalized mouse podocytes. Exogenous TGF-beta(1)-induced podocyte apoptosis through caspase-3 activation, which was related to elevated ROS levels generated by selective upregulation of NADPH oxidase 4 (Nox4). In mouse podocytes, Nox4 was predominantly localized to mitochondria, and Nox4 upregulation by TGF-beta(1) markedly depolarized mitochondrial membrane potential. TGF-beta(1)-induced ROS production and caspase activation were mitigated by an antioxidant, the Nox inhibitor diphenyleneiodonium, or small interfering RNA for Nox4. A TGF-beta receptor I blocker, SB-431542, completely reversed the changes triggered by TGF-beta(1). Knockdown of either Smad2 or Smad3 prevented the increase of Nox4 expression, ROS generation, loss of mitochondrial membrane potential, and caspase-3 activation by TGF-beta(1). These results suggest that TGF-beta(1)-induced mitochondrial Nox4 upregulation via the TGF-beta receptor-Smad2/3 pathway is responsible for ROS production, mitochondrial dysfunction, and apoptosis, which may at least in part contribute to the development and progression of proteinuric glomerular diseases such as diabetic nephropathy.