Abstract
Purpose Fushen Granule (FSG) is a Chinese medicine prepared by doctors for treating patients with chronic renal failure, which is usually accompanied by gastrointestinal dysfunction. Here, we explore the protective effect of FSG on intestinal barrier injury in chronic renal failure through bioinformatic analysis and experimental verification. Methods In this study, information on the components and targets of FSG related to CRF is collected to construct and visualize protein-protein interaction networks and drug-compound-target networks using network pharmacological methods. DAVID is used to conduct gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Then, it is validated by in vitro experiments. In this study, the human intestinal epithelial (T84) cells are used and divided into four groups: control group, model group, FSG low-dose group, and FSG high-dose group. After the experiment, the activity of T84 cells is detected by a MTT assay, and the expressions of tight junction protein ZO-1, claudin-1, nuclear factor erythroid 2-related factor (Nrf2), heme oxygenase-1 (HO-1), malondialdehyde (MDA), and cyclooxygenase-2 (COX-2) are examined by immunofluorescence and/or western blotting. Results Eighty-six potential chronic renal failure-related targets are identified by FSG; among them, nine core genes are screened. Furthermore, GO enrichment analysis shows that the cancer-related signaling pathway, the PI3K-Akt signaling pathway, the HIF1 signaling pathway, and the TNF signaling pathway may play key roles in the treatment of CRF by FSG. The MTT method showed that FSG is not cytotoxic to uremic toxin-induced injured T84 cells. The results of immunofluorescence and WB indicate that compared with the control group, protein expressions level of ZO-1, claudin-1, and Nrf2 in T84 cells is decreased and protein expressions level of HO-1, MDA, and COX-2 is increased after urinary toxin treatment. Instead, compared with the model group, protein expressions level of ZO-1, claudin-1, and Nrf2 in T84 cells is increased and protein expressions level of HO-1, MDA, and COX-2 is decreased after FSG treatment. Conclusion FSG had a protective effect on urinary toxin-induced intestinal epithelial barrier injury in chronic renal failure, and its mechanism may be related to the upregulation of Nrf2/HO-1 signal transduction and the inhibition of tissue oxidative stress and inflammatory responses. Screening CRF targets and identifying the corresponding FSG components by network pharmacological methods is a practical strategy to explain the mechanism of FSG in improving gastrointestinal dysfunction in CRF.
Highlights
Chronic kidney disease (CKD) is a kind of renal disease featuring chronic renal dysfunction and structural damage.e glomerular filtration rate (GFR) is the best index reflecting overall kidney function [1]
A large number of studies have reported that the accumulation of urinary toxins and the influx of other residual toxins destroy the intestinal epithelial barrier, allowing the entry of intestinal bacteria into the blood, which further aggravates the progression of chronic renal failure (CRF) [4, 5], and end-stage renal disease (ESRD) develops
Each Fushen Granule (FSG) component was input into the TCMSP for screening
Summary
Chronic kidney disease (CKD) is a kind of renal disease featuring chronic renal dysfunction and structural damage.e glomerular filtration rate (GFR) is the best index reflecting overall kidney function [1]. E renal function of CKD patients gradually decreases due to nitrogen waste accumulation, which is discharged by normal persons over time and eventually progresses to chronic renal failure (CRF), which is always. The content of enterotoxins such as para-cresol sulfate (PCS) and indole sulfate (IS) was significantly increased in the serum of CKD patients and long-term dialysis patients, indicating increased intestinal permeability [7, 8]. In CKD and long-term dialysis patients with damaged intestinal epithelial barriers, intestinal bacterial DNA and uremia-related toxins infiltrate the blood from the intestinal tract, and white blood cells in the blood are activated. Erefore, the level of endotoxin from the gut flora in patients with CFR is significantly related to intestinal dysfunction. Kim [12] found that the elimination of uremic toxins was an effective treatment for low-turnover osteopathy in CKD patients. erefore, an important way to improve the nutritional status and quality of life of uremic patients is to regulate intestinal dysfunction
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