Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease. TGF-β1/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.

中文翻译：

---

Smad4通过调节糖酵解和OXPHOS促进糖尿病性肾病。

糖尿病肾病（DN）是终末期肾脏疾病的主要原因。TGF-β1/ Smad3信号在DN中起主要病理作用。但是，尚未研究Smad4的贡献。使用抗Smad4锁定核酸的肾脏Smad4耗竭阻止了2型DN小鼠的进行性足细胞损伤和肾小球硬化，提示Smad4在足细胞中具有致病作用。在DN期间，Smad4在人和小鼠足细胞中上调。足细胞中有条件的Smad4缺失保护小鼠免受2型DN的影响，而与肥胖无关。从机制上讲，高血糖症会导致Smad4定位于足细胞中的线粒体，从而导致糖酵解和氧化磷酸化降低，以及活性氧的产生增加。这部分地起作用 通过将Smad4直接与糖酵解酶PKM2结合并还原PKM2的活性四聚体形式。此外，Smad4与ATPIF1相互作用，导致ATPIF1降解的减少。总之，我们发现了Smad4引起糖尿病足细胞损伤的线粒体机制。