Objective and design

Macrophages exhibit strong phenotypic plasticity and can mediate renal inflammation by polarizing into an M1 phenotype. They play a pivotal role in diabetic nephropathy (DN). Here, we have investigated the regulatory role of transforming growth factor β-activated kinase 1-binding protein 1 (TAB1) in glycolysis and activation of macrophages during DN.

Methods

TAB1 was inhibited using siRNA in high glucose (HG)-stimulated bone marrow-derived macrophages (BMMs) and lentiviral vector-mediated TAB1 knockdown was used in streptozotocin (STZ)-induced diabetic mice. Western blotting, flow cytometry, qRT-PCR, ELISA, PAS staining and immunohistochemical staining were used for assessment of TAB1/nuclear factor-κB (NF-κB)/hypoxia-inducible factor-1α (HIF-1α), iNOS, glycolysis, inflammation and the clinical and pathological manifestations of diabetic nephropathy.

Results

We found that TAB1/NF-κB/HIF-1α, iNOS and glycolysis were up-regulated in BMMs under HG conditions, leading to release of further inflammatory factors, Downregulation of TAB1 could inhibit glycolysis/polarization of macrophages and inflammation in vivo and in vitro. Furthermore, albuminuria, the tubulointerstitial damage index and glomerular mesangial expansion index of STZ-induced diabetic nephropathy mice were decreased by TAB1 knockdown.

Conclusions

Our results suggest that the TAB1/NF-κB/HIF-1α signaling pathway regulates glycolysis and activation of macrophages in DN.

中文翻译：

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TAB1 调节糖尿病肾病中巨噬细胞的糖酵解和活化

目标与设计

巨噬细胞表现出很强的表型可塑性，并且可以通过极化为 M1 表型来介导肾脏炎症。它们在糖尿病肾病 (DN) 中起关键作用。在这里，我们研究了 DN 期间转化生长因子 β 活化激酶 1 结合蛋白 1 (TAB1) 在糖酵解和巨噬细胞活化中的调节作用。

方法

在高葡萄糖 (HG) 刺激的骨髓衍生巨噬细胞 (BMM) 中使用 siRNA 抑制 TAB1，并在链脲佐菌素 (STZ) 诱导的糖尿病小鼠中使用慢病毒载体介导的 TAB1 敲低。Western印迹、流式细胞术、qRT-PCR、ELISA、PAS染色和免疫组织化学染色用于评估TAB1/核因子-κB (NF-κB)/缺氧诱导因子-1α (HIF-1α)、iNOS、糖酵解、炎症和糖尿病肾病的临床和病理表现。

结果

我们发现，在 HG 条件下，BMMs 中 TAB1/NF-κB/HIF-1α、iNOS 和糖酵解上调，导致更多炎症因子的释放，TAB1 的下调可以抑制体内和体内巨噬细胞的糖酵解/极化和炎症。体外。此外，TAB1 敲低可降低 STZ 诱导的糖尿病肾病小鼠的白蛋白尿、肾小管间质损伤指数和肾小球系膜扩张指数。

结论

我们的结果表明 TAB1/NF-κB/HIF-1α 信号通路调节 DN 中巨噬细胞的糖酵解和活化。