Micheliolide ameliorates diabetic kidney disease by inhibiting Mtdh-mediated renal inflammation in type 2 diabetic db/db mice
Micheliolide ameliorates diabetic kidney disease by inhibiting Mtdh-mediated renal inflammation in type 2 diabetic db/db mice
复制标题
Micheliolide 通过抑制 2 型糖尿病 db/db 小鼠 Mtdh 介导的肾脏炎症来改善糖尿病肾病
DOI：
10.1016/j.phrs.2019.104506
复制
发表时间：
2019-12-01
影响因子：
9.3
通讯作者：
Long, Haibo
中科院分区：
文献类型：
--
作者：
Liu, Wenting;Chen, Xiaowen;Long, Haibo
Diabetic kidney disease (DKD) is the principal cause of end-stage renal disease worldwide and few treatments are available. Because immunomodulators are pivotal to DKD pathophysiology, anti-inflammatory agents may be useful for treating DKD. This study was conducted to investigate the effect of micheliolide (MCL), a novel guaianolide sesquiterpene lactone with well-known anti-inflammatory effects, on DKD. Treatment with dimethylaminomicheliolide (DMAMCL), the pro-drug of MCL currently under clinical trial in oncology, protected the kidneys against proteinuria, renal failure, histopathological injury, and inflammation in db/db mice. This effect was associated with metadherin (Mtdh) downregulation. We observed aberrant upregulation of Mtdh in the kidneys of db/db mice and high-glucose (HG)-induced mouse tubular epithelial cells (mTECs). Downregulation of Mtdh obviously inhibited nuclear factor-kappa B signaling activation and suppressed its downstream inflammatory cytokines, such as monocyte chemotactic peptide-1, interleukin-1 beta, tumor necrosis factor-alpha, and interleukin-6 in HG-induced mTECs, which was similar to the effect of MCL. Mtdh overexpression largely reversed the anti-inflammatory role of MCL. Moreover, MCL down-regulated Mtdh by both inhibiting the transcription level and promoting ubiquitin-mediated degradation. These findings suggest that DMAMCL is a promising anti-inflammatory agent useful for preventing renal injury in DKD by inhibiting Mtdh-mediated renal inflammation.
