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Anti-apoptosis mechanism of triptolide based on network pharmacology in focal segmental glomerulosclerosis rats
Yayu Li1, Xue Jiang1, Litao Song2
1Department of Nephrology, Guangxing Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou Hospital of Traditional Chinese Medicine, No. 453, Tiyuchang Road, Hangzhou City, Zhejiang Province 310007, P. R. China.
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.
Insights
Triptolide (TPL) protects against kidney injury in focal segmental glomerulosclerosis (FSGS) by inhibiting podocyte apoptosis. TPL targets Interleukin-4 (IL4), reducing cell death and preserving kidney function in FSGS rats.
Area of Science:
- Pharmacology
- Nephrology
- Molecular Biology
Background:
- Triptolide (TPL), derived from Tripterygium wilfordii, possesses known anti-cancer and antioxidant properties.
- Focal segmental glomerulosclerosis (FSGS) is a significant cause of kidney disease characterized by podocyte injury and apoptosis.
- The precise mechanism by which TPL exerts protective effects in FSGS remains to be fully elucidated.
Purpose of the Study:
- To investigate the anti-apoptotic mechanism of Triptolide (TPL) in focal segmental glomerulosclerosis (FSGS).
- To validate the findings through network pharmacology and experimental models in vivo and in vitro.
- To identify key molecular targets and pathways involved in TPL's therapeutic action in FSGS.
Main Methods:
- Network pharmacology analysis was conducted using databases like TCMSP, GeneCards, and OMIM to identify TPL targets in FSGS.
- Protein-protein interaction (PPI) networks were constructed and analyzed using STRING and Cytoscape to identify hub genes.
- In vivo (rat FSGS model) and in vitro (rat podocytes) experiments utilized CCK8, TUNEL, and Western blot assays to validate TPL's effects on apoptosis and protein expression.
Main Results:
- Network pharmacology identified Interleukin-4 (IL4) as a key target of TPL in FSGS, enriched in cell apoptosis and p53 signaling pathways.
- TPL significantly inhibited FSGS-induced apoptosis in rat kidneys and podocytes, regulating IL4, nephrin, podocin, and p53 protein levels.
- TPL reversed the pro-apoptotic effects of IL4 overexpression and increased nephrin/podocin expression while decreasing p53 levels in rat podocytes.
Conclusions:
- Triptolide (TPL) demonstrates a protective effect against kidney injury in focal segmental glomerulosclerosis (FSGS) by inhibiting podocyte apoptosis.
- The mechanism involves TPL targeting Interleukin-4 (IL4), thereby modulating critical pathways related to cell survival and apoptosis.
- These findings highlight TPL as a potential therapeutic agent for FSGS, offering a novel approach to kidney disease management.
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