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Qing-Re-Xiao-Zheng Formula Modulates Gut Microbiota and Inhibits Inflammation in Mice With Diabetic Kidney Disease.

ABSTRACT: Evidence indicates that the metabolic inflammation induced by gut microbiota dysbiosis contributes to diabetic kidney disease. Prebiotic supplementations to prevent gut microbiota dysbiosis, inhibit inflammatory responses, and protect the renal function in DKD. Qing-Re-Xiao-Zheng formula (QRXZF) is a Traditional Chinese Medicine (TCM) formula that has been used for DKD treatment in China. Recently, there are growing studies show that regulation of gut microbiota is a potential therapeutic strategy for DKD as it is able to reduce metabolic inflammation associated with DKD. However, it is unknown whether QRXZF is effective for DKD by regulating of gut microbiota. In this study, we investigated the reno-protective effect of QRXZF by exploring its potential mechanism between gut microbiota and downstream inflammatory pathways mediated by gut-derived lipopolysaccharide (LPS) in the kidney. High-fat diet (HFD) and streptozotocin injection-induced DKD mice model was established to assess the QRXZF effect in vivo. Mice treated with QRXZF for 8 weeks had significantly lower levels of urinary albumin, serum cholesterol and triglycerides. The renal injuries observed through histological analysis were attenuated as well. Also, mice in the QRXZF group had higher levels of Zonula occludens protein-1 (ZO-1) expression, lower levels of serum fluorescein-isothiocyanate (FITC)-dextran and less-damaged colonic mucosa as compared to the DKD group, implying the benefit role for the gut barrier integrity. QRXZF treatment also reversed gut dysbiosis and reduced levels of gut-derived LPS. Notably, the expression of toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB), which are important inflammation pathways in DKD, were suppressed in the QRXZF groups. In conclusion, our results indicated that the reno-protective effects of QRXZF was probably associated with modulating gut microbiota and inhibiting inflammatory responses in the kidney.

SUBMITTER: Gao Y

PROVIDER: S-EPMC8481597 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Introduction: Qing-Re-Xiao-Zheng-Yi-Qi Formula is an effective prescription in diabetic kidney disease treatment, we have confirmed the efficacy of Qing-Re-Xiao-Zheng therapy in diabetic kidney disease through clinical trials. In this study, we investigated the mechanisms of Qing-Re-Xiao-Zheng-Yi-Qi Formula in the treatment of diabetic kidney disease. Methods: We used Vanquish UHPLCTM to analyze the chemical profiling of Qing-Re-Xiao-Zheng-Yi-Qi Formula freeze-dried powder. We constructed diabetic kidney disease rat models induced by unilateral nephrectomy and high-dose streptozocin injection. We examined blood urea nitrogen, serum creatinine, serum glucose, total cholesterol, triglyceride, serum total protein, albumin, alanine aminotransferase, aspartate aminotransferase and 24 h urinary total protein in diabetic kidney disease rats. The renal pathological changes were observed by HE, Masson, PAS stanning and transmission electron microscopy. The levels of fibrosis-related proteins and mitophagy-related proteins were detected by western blot analysis. We also conducted an immunofluorescence co-localization analysis on podocytes to further investigate the effect of Qing-Re-Xiao-Zheng-Yi-Qi Formula treatment on mitophagy. Results: A total of 27 constituents in Qing-Re-Xiao-Zheng-Yi-Qi Formula were tentatively identified. We found PINK1/Parkin-mediated mitophagy was inhibited in diabetic kidney disease. Qing-Re-Xiao-Zheng-Yi-Qi Formula treatment could raise body weight and reduce renal index, reduce proteinuria, improve glycolipid metabolic disorders, ameliorate renal fibrosis, and reduce the expression of Col Ⅳ and TGF-β1 in diabetic kidney disease rats. Qing-Re-Xiao-Zheng-Yi-Qi Formula treatment could also increase the expression of nephrin, activate mitophagy and protect podocytes in diabetic kidney disease rats and high glucose cultured podocytes. Conclusion: PINK1/Parkin-mediated mitophagy was inhibited in diabetic kidney disease, and Qing-Re-Xiao-Zheng-Yi-Qi Formula treatment could not only ameliorate pathological damage, but also promote mitophagy to protect podocytes in diabetic kidney disease.

Project description:BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing lung disease with high mortality. Inflammation and epithelial mesenchymal transformation (EMT) may play an important role in the occurrence and development of IPF. Qing-Re-Huo-Xue formula (QRHXF) has been used clinically by our team for half a century and has obvious therapeutic effects on lung disease. Nevertheless, the role and mechanism of QRHXF in the treatment of IPF have never been studied.MethodsA mouse pulmonary fibrosis model was established by intratracheal injection of BLM. The effects of QRHXF on the treatment of pulmonary fibrosis were studied by pulmonary function testing, imaging examination, pathological staining, transmission electron microscopy (TEM) observation and mRNA expression. Tandem mass tag (TMT)-based quantitative proteomics was carried out to analyse the lung protein expression profiles between the control (CTL), bleomycin (BLM) and QRHXF (BLM + QRHXF) groups. Immunohistochemistry and qRT-PCR were used to verify the possible existence of drug target proteins and signalling pathways.ResultsThe results of pulmonary function, lung pathology and imaging examinations showed that QRHXF could significantly alleviate BLM-induced pulmonary fibrosis in vivo. Additionally, inflammatory cell infiltration and EMT were markedly reduced in BLM-induced PF mice administered QRHXF. Proteomics detected a total of 35 proteins, of which 17 were upregulated and 18 were downregulated. A total of 19 differentially expressed proteins (DEPs) overlapped between the BLM versus CTL groups and the BLM + QRHXF versus BLM groups. The expression of p53 and IGFBP3 was reversed in the QRHXF intervention group, which was verified by immunohistochemistry and qRT-PCR.ConclusionsQRHXF attenuated BLM-induced pulmonary fibrosis, and regulation of the p53/IGFBP3 pathway might be associated with its efficacy, which holds promise as a novel treatment strategy for pulmonary fibrosis patients.

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Qing-Re-Xiao-Zheng Formula Modulates Gut Microbiota and Inhibits Inflammation in Mice With Diabetic Kidney Disease.

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