Empagliflozin improves diabetic renal tubular injury by alleviating mitochondrial fission via AMPK/SP1/PGAM5 pathway
Empagliflozin improves diabetic renal tubular injury by alleviating mitochondrial fission via AMPK/SP1/PGAM5 pathway
复制标题
DOI：
10.1016/j.metabol.2020.154334
复制
发表时间：
2020-10-01
影响因子：
9.8
通讯作者：
Chen, Liming
中科院分区：
文献类型：
--
作者：
Liu, Xiangyang;Xu, Chaofei;Chen, Liming
背景与目的：线粒体过多！在糖尿病肾病（DKD）中观察到裂变。磷酸甘油酸变位酶家族成员 5 (PGAM5) 通过使动力相关蛋白 1 Ser637 (DRP1S637) 去磷酸化，在线粒体裂变中发挥重要作用。 PGAM5是否参与线粒体！糖尿病肾小管损伤中的裂变尚不清楚。临床试验观察到钠m-葡萄糖协同转运蛋白2（SGLT2）抑制剂对DKD具有令人鼓舞的作用，但其机制仍不清楚。实验方法：我们使用KK-Ay小鼠作为糖尿病模型，并通过口服灌胃给予恩格列净（Empa）。检测线粒体分裂以及磷酸化AMP激活蛋白激酶（p-AMPK）、特异性蛋白1（SP1）、PGAM5和DRP1S637的表达。我们还检查了在正常葡萄糖（NG）、高葡萄糖（HG）和高葡萄糖+Empa（HG Empa）环境中培养的HK2细胞的这些变化。然后我们使用 AMPK 激活剂（5-氨基咪唑-4-甲酰亚胺核苷，AICAR）、抑制剂（化合物 C）、si-SP1 和 si-PGAM5 验证了我们的推论。最后，我们通过CHIP实验证实了SP1和PGAM5启动子之间的相互作用。主要结果：在糖尿病或HG环境下，线粒体分裂以及SP1、PGAM 5 的表达增加，p-AMPK、DRP1S637 的表达减少。这些变化在 Empa 或 AICAR 治疗组中全部逆转。化合物 C 可以减弱 Empa 的这些逆转作用。si-SP1 或 si-PGAM5 都可以减轻线粒体裂变，而不影响 AMPK 磷酸化。最后，CHIP实验证实了SPI与PGAM5启动子之间的相互作用。结论与启示：PGAM5加重了糖尿病肾小管损伤的发生，而Empa可以通过AMPK/SP1/PGAM5通路减轻线粒体分裂来改善DKD。 (C) 2020 作者。由爱思唯尔公司出版
Background and purpose: Excessive mitochondria! fission was observed in diabetic kidney disease (DKD). Phosphoglycerate mutase family member 5 (PGAM5) plays an important role in mitochondrial fission by dephosphorylating the dynamin-related protein 1 at Ser637 (DRP1S637). Whether PGAM5 participates in the mitochondria! fission in diabetic renal tubular injury is unknown. Clinical trials have observed encouraging effect of Sodiu m-glucose cotransporter 2 (SGLT2) inhibitors on DKD though the underling mechanisms remain unclear.Experimental approach: We used KK-Ay mice as diabetic model and Empagliflozin (Empa) were administrated by oral gavage. The mitochondrial fission and the expressions of phosphorylated AMP-activated protein kinase (p-AMPK), specificityproteinl (SP1), PGAM5 and DRP1S637 were tested. We also examined these changes in HK2 cells that cultured in normal glucose (NG), high glucose (HG) and high glucose +Empa (HG Empa) environment. Then we verified our deduction using AMPK activator (5-aminoimidazole-4-carboximide Riboside, AICAR), inhibitor (Compound C), si-SP1 and si-PGAM5. Lastly, we testified the interaction between SP1 and the PGAM5promotor by CHIP assay.Key results:The mitochondrial fission and the expression of SP1 , PGAM 5 increased and the expression of p-AMPK, DRP1S637 decreased in diabetic or HG environment. These changes were all reversed in Empa or AICAR treated groups. These reversal effects of Empa could be diminished by Compound C. Either si-SP1 or si-PGAM5 could alleviate the mitochondrial fission without affection on AMPK phosphorylation. Finally, the CHIP assay confirmed the interaction between SPI and the PGAM5 promotor.Conclusions and implications: The PGAM5 aggravated the development of diabetic renal tubular injury and the Empa could improve the DKD by alleviating mitochondrial fission via AMPK/SP1/PGAM5 pathway. (C) 2020 The Authors. Published by Elsevier Inc.