NIX-mediated mitophagy protects against proteinuria-induced tubular cell apoptosis and renal injury
NIX-mediated mitophagy protects against proteinuria-induced tubular cell apoptosis and renal injury
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NIX 介导的线粒体自噬可防止蛋白尿诱导的肾小管细胞凋亡和肾损伤
DOI：
10.1152/ajprenal.00360.2018
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通讯作者：
Zhang W
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作者：
Xu D;Chen P;Wang B;Wang Y;Miao N;Yin F;Chen Q;Zhou Z;Xie H;Zhou L;Liu J;Wang X;Zent R;Lu L;Zhang W
蛋白尿是肾损伤最常见的症状，是肾小管损伤的独立因素。然而，其基本机制仍有待充分阐明。线粒体是蛋白尿致肾小管细胞损伤的重要靶点。线粒体自噬不足通过启动线粒体功能障碍相关的细胞凋亡而加剧细胞损伤。在实验中，研究了NIP3样蛋白X（NIX）介导的线粒体自噬在蛋白尿诱导的肾损伤中的作用。在这项研究中，我们证明了NIX在肾小管中的表达减少，并且与患者的估计肾小球滤过率的下降和蛋白尿的增加相关。在蛋白尿小鼠中，NIX介导的线粒体自噬被显著抑制。同时，蛋白尿小鼠表现出肾功能不全，线粒体碎片增加，肾小管细胞凋亡。NIX的过表达减弱了蛋白尿小鼠的这些破坏。在培养的肾小管上皮细胞中，白蛋白诱导NIX介导的线粒体自噬减少和细胞凋亡增加。NIX的过表达减弱了白蛋白诱导的细胞凋亡，而NIX siRNA加重了这些扰动。这些结果表明，蛋白尿抑制了肾小管上皮细胞中的NIX介导的线粒体自噬，这触发了细胞经历依赖于细胞凋亡的细胞。总的来说，我们的研究结果表明，恢复NIX介导的线粒体自噬可能是一个新的治疗靶点，以减轻蛋白尿诱导的肾损伤。
Proteinuria, the most common symptom of renal injury, is an independent factor for renal tubular injury. However, the underlying mechanism remains to be fully elucidated. Mitochondrion is an important target for proteinuria-induced renal tubular cell injury. Insufficient mitophagy exacerbates cell injury by initiating mitochondrial dysfunction-related cell apoptosis. In the experiment, the role of NIP3-like protein X (NIX)-mediated mitophagy was investigated in proteinuria-induced renal injury. In this study, we demonstrated that NIX expression was reduced in renal tubules and correlated with the decline of estimated glomerular filtration rate and increase of the proteinuria in patients. In proteinuric mice, NIX-mediated mitophagy was significantly suppressed. Meanwhile, the proteinuric mice exhibited renal dysfunction, increased mitochondrial fragmentation, and tubular cell apoptosis. Overexpression of NIX attenuated those disruptions in proteinuric mice. In cultured renal tubular epithelial cells, albumin induced a decrease in NIX-mediated mitophagy and an increase in cell apoptosis. Overexpression of NIX attenuated albumin-induced cell apoptosis, whereas NIX siRNA aggravated these perturbations. These results indicate that proteinuria suppresses NIX-mediated mitophagy in the renal tubular epithelial cell, which triggers the cell undergoing mitochondria-dependent cell apoptosis. Collectively, our finding suggests that restoration of NIX-mediated mitophagy might be a novel therapeutic target for alleviating proteinuria-induced kidney injury.