Zuogui-Jiangtang-Yishen decoction prevents diabetic kidney disease: Intervene pyroptosis induced by trimethylamine n-oxide through the mROS-NLRP3 axis

Background: Nowadays, diabetic kidney disease (DKD) has become one of the most threatening to the end-stage renal diseases, and the early prevention of DKD is inevitable for Diabetes Mellitus (DM) patients. 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.