Abstract | BACKGROUND: AIMS: Pyroptosis, a programmed cell death that mediates renal inflammation induced early renal injury. The trimethylamine n-oxide ( TMAO) was also an independent risk factor for renal injury. Here, the associations between TMAO-induced pyroptosis and pathogenesis of DKD were studied, and the potential mechanism of Zuogui-Jiangtang- Yishen (ZGJTYS) decoction to prevent DKD was further investigated. METHOD: Using Goto-Kakizaki (GK) rats to establish the early DKD models. The 16S-ribosomal RNA ( 16S rRNA) sequencing, fecal fermentation and UPLC-MS targeted metabolism techniques were combined to explore the changes of gut-derived TMAO level under the background of DKD and the effects of ZGJTYS. The proximal convoluted tubule epithelium of human renal cortex (HK-2) cells was adopted to explore the influence of pyroptosis regulated by TMAO. RESULTS: It was demonstrated that ZGJTYS could prevent the progression of DKD by regulating glucolipid metabolism disorder, improving renal function and delaying renal pathological changes. In addition, we illustrated that gut-derived TMAO could promote DKD by activating the mROS-NLRP3 axis to induce pyroptosis. Furthermore, besides interfering with the generation of TMAO through gut microbiota, ZGJTYS inhibited TMAO-induced pyroptosis with a high- glucose environment and the underlying mechanism was related to the regulation of mROS-NLRP3 axis. CONCLUSION: Our results suggested that ZGJTYS inhibited the activation of pyroptosis by gut-derived TMAO via the mROS-NLRP3 axis to prevent DKD.
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Authors | Zi-Yang Yi, Ya-Jun Peng, Bo-Ping Hui, Zhao Liu, Qing-Xia Lin, Di Zhao, Yan Wang, Xiu Liu, Jing Xie, Shui-Han Zhang, Jian-Hua Huang, Rong Yu |
Journal | Phytomedicine : international journal of phytotherapy and phytopharmacology
(Phytomedicine)
Vol. 114
Pg. 154775
(Jun 2023)
ISSN: 1618-095X [Electronic] Germany |
PMID | 36990008
(Publication Type: Journal Article)
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Copyright | Copyright © 2023. Published by Elsevier GmbH. |
Chemical References |
- NLR Family, Pyrin Domain-Containing 3 Protein
- Nlrp3 protein, rat
- RNA, Ribosomal, 16S
- trimethyloxamine
- yishen
- zuogui
- Drugs, Chinese Herbal
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Topics |
- Animals
- Humans
- Rats
- Chromatography, Liquid
- Diabetes Mellitus
- Diabetic Nephropathies
- NLR Family, Pyrin Domain-Containing 3 Protein
(metabolism)
- Pyroptosis
- RNA, Ribosomal, 16S
- Tandem Mass Spectrometry
- Drugs, Chinese Herbal
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