Anti-apoptosis mechanism of triptolide based on network pharmacology in focal segmental glomerulosclerosis rats.

Yayu Li,Mengdie Yang,Jing Pan,Litao Song,Xue Jiang

doi:10.1042/bsr20192920

Abstract

Triptolide (TPL), the active component of Tripterygium wilfordii, exhibits anti-cancer and antioxidant functions. We aimed to explore the anti-apoptosis mechanism of TPL based on network pharmacology and in vivo and in vitro research validation using a rat model of focal segmental glomerulosclerosis (FSGS). The chemical structures and pharmacological activities of the compounds reported in T. wilfordii were determined and used to perform the network pharmacology analysis. The Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) was then used to identify the network targets for 16 compounds from Tripterygium wilfordii. Our results showed that 47 overlapping genes obtained from the GeneCards and OMIM databases were involved in the occurrence and development of FSGS and used to construct the protein–protein interaction (PPI) network using the STRING database. Hub genes were identified via the MCODE plug-in of the Cytoscape software. IL4 was the target gene of TPL in FSGS and was mainly enriched in the cell apoptosis term and p53 signaling pathway, according to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. TPL inhibited FSGS-induced cell apoptosis in rats and regulated IL4, nephrin, podocin, and p53 protein levels via using CCK8, TUNEL, and Western blot assays. The effects of IL4 overexpression, including inhibition of cell viability and promotion of apoptosis, were reversed by TPL. TPL treatment increased the expression of nephrin and podocin and decreased p53 expression in rat podocytes. In conclusion, TPL inhibited podocyte apoptosis by targeting IL4 to alleviate kidney injury in FSGS rats.

Highlights

Focal segmental glomerulosclerosis (FSGS) is a clinical pathological syndrome, and its typical pathological feature is sclerosing lesions in the focal glomeruli and in the glomerular segment
IL4 obtained from the most significant module of the protein–protein interaction (PPI) network was verified as a key by using the Molecular Complex Detection (MCODE) plug-in of Cytoscape software, and it was found to be involved in FSGS (Figure 1B–D)
Glomerular sclerosis is the final pathological change in FSGS caused by the excessive accumulation of the glomerular extracellular matrix (ECM)

Summary

Introduction

Focal segmental glomerulosclerosis (FSGS) is a clinical pathological syndrome, and its typical pathological feature is sclerosing lesions in the focal glomeruli and in the glomerular segment. The clinical manifestations of FSGS patients are massive proteinuria, hematuria, hypertension, and progressive decrease in renal function. The condition of 3.6% of patients with end-stage renal disease developed from FSGS [1,2]. The main clinical therapies for FSGS are immunologic drugs, glucocorticoids, and blockers of the renin–angiotensin system; their therapeutic effects are not satisfactory. TPL has anti-inflammatory, anti-tumor, and immunologic effects on many diseases [4]. TPL inhibits the secretion of many cytokines, adhesion molecules, and chemokines and affects the functions of various cells, including dendritic cells and renal tubular epithelial cells [5,6]. TPL has been reported to alleviate the progression of glomerulosclerosis and the excretion rate of urinary albumin to inhibit the progression

Objectives

Methods

Results

Conclusion