Smad4 promotes diabetic nephropathy by modulating glycolysis and OXPHOS
Smad4 promotes diabetic nephropathy by modulating glycolysis and OXPHOS
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Smad4 通过调节糖酵解和 OXPHOS 促进糖尿病肾病
DOI：
10.15252/embr.201948781
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发表时间：
2020-01-09
期刊：
影响因子：
7.7
通讯作者：
Yu, Xueqing
中科院分区：
文献类型：
--
作者：
Li, Jinhua;Sun, Yu Bo Yang;Yu, Xueqing
糖尿病肾病（DN）是终末期肾病的主要原因。TGF-β 1/Smad 3信号转导在DN中起主要病理作用;然而，Smad 4的贡献尚未被研究。使用抗Smad 4锁核酸在肾脏中的Smad 4消耗停止了小鼠2型DN中进行性足细胞损伤和肾小球硬化，表明Smad 4在足细胞中的致病作用。Smad 4在DN期间在人类和小鼠足细胞中上调。足细胞中的条件性Smad 4缺失保护小鼠免受2型DN，与肥胖无关从机制上讲，高血糖症诱导Smad 4定位于足细胞中的线粒体，导致糖酵解和氧化磷酸化减少，活性氧产生增加。这部分地通过Smad 4与糖酵解酶PKM 2的直接结合并还原PKM 2的活性四聚体形式来起作用。此外，Smad 4与ATPIF 1相互作用，导致ATPIF 1降解减少。总之，我们发现了Smad 4引起糖尿病足细胞损伤的线粒体机制。
Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease. TGF-beta 1/Smad3 signalling plays a major pathological role in DN; however, the contribution of Smad4 has not been examined. Smad4 depletion in the kidney using anti-Smad4 locked nucleic acid halted progressive podocyte damage and glomerulosclerosis in mouse type 2 DN, suggesting a pathogenic role of Smad4 in podocytes. Smad4 is upregulated in human and mouse podocytes during DN. Conditional Smad4 deletion in podocytes protects mice from type 2 DN, independent of obesity. Mechanistically, hyperglycaemia induces Smad4 localization to mitochondria in podocytes, resulting in reduced glycolysis and oxidative phosphorylation and increased production of reactive oxygen species. This operates, in part, via direct binding of Smad4 to the glycolytic enzyme PKM2 and reducing the active tetrameric form of PKM2. In addition, Smad4 interacts with ATPIF1, causing a reduction in ATPIF1 degradation. In conclusion, we have discovered a mitochondrial mechanism by which Smad4 causes diabetic podocyte injury.