Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University , Shanghai , China.
Department of Nephrology, Shanghai Tong Ren Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , China.
Am J Physiol Renal Physiol. 2019 Feb 1;316(2):F382-F395. doi: 10.1152/ajprenal.00360.2018. Epub 2018 Sep 12.
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.
蛋白尿是肾脏损伤最常见的症状，也是肾小管损伤的独立因素。然而，其潜在机制仍有待充分阐明。线粒体是蛋白尿诱导的肾小管细胞损伤的重要靶点。自噬不足通过引发与线粒体功能障碍相关的细胞凋亡而加重细胞损伤。在实验中，研究了 NIP3 样蛋白 X（NIX）介导的自噬在蛋白尿诱导的肾脏损伤中的作用。本研究表明，NIX 在肾小管中的表达减少，与患者肾小球滤过率下降和蛋白尿增加有关。在蛋白尿小鼠中，NIX 介导的自噬明显受到抑制。同时，蛋白尿小鼠表现出肾功能障碍、线粒体片段增加和肾小管细胞凋亡。在蛋白尿小鼠中过表达 NIX 可减轻这些破坏。在培养的肾小管上皮细胞中，白蛋白诱导 NIX 介导的自噬减少和细胞凋亡增加。过表达 NIX 可减轻白蛋白诱导的细胞凋亡，而 NIX siRNA 则加剧了这些干扰。这些结果表明，蛋白尿抑制了肾小管上皮细胞中 NIX 介导的自噬，从而触发了依赖线粒体的细胞凋亡。总之，我们的发现表明，恢复 NIX 介导的自噬可能是缓解蛋白尿诱导的肾脏损伤的新治疗靶点。
