Allium macrostemon Bge. delays chronic renal failure by modulating IL-17 signaling pathway and affecting tryptophan/glycerophospholipid metabolism.

ETHNOPHARMACOLOGICAL RELEVANCE: In traditional Chinese medicine (TCM), Allium macrostemon Bge. (AMB) is characterized as warm-natured, acrid-bitter, and frequently employed to treat disorders associated with imbalances in water metabolism, such as edema. Modern pharmacological studies have shown that AMB has anti-atherosclerotic, hypolipidemic, anti-inflammatory and antioxidant effects. Chronic renal failure (CRF), one of the most prevalent chronic diseases worldwide, is categorized within the "edema" spectrum and poses a significant challenge to global healthcare systems, with its progression closely associated with inflammation. However, the role and mechanism of action of AMB in delaying CRF have not been fully investigated.

AIM OF THE STUDY: This study aimed to investigate the improvement effect of AMB on CRF and the potential mechanism by in vitro and in vivo experiments.

MATERIALS AND METHODS: In vitro experiments, the effective part of AMB was screened through the MPC5 cell injury model induced by Adriamycin (ADM), and the efficacy was verified in the HK-2 cell model. The delaying effect of the n-butanol fraction (NF) on CRF rats was studied by UPLC-MS/MS combined with high-throughput screening. RNA-seq and bioinformatics techniques were used to analyze the differentially expressed genes (DEGs) and pathways in MPC5 cells. Molecular docking was used to verify the interaction between the components entering the blood and the key pathway proteins. In vivo experiments were conducted by intragastric administration of adenine for 3 weeks to establish a CRF rat model. Niaoduqing granules (NDQG) was used as the positive control. Different concentrations of the active components were intragastrically administered for 4 weeks. The pathological damage of the kidneys was evaluated by HE and Masson staining. The disease indicators and pathway protein levels were detected by ELISA and immunohistochemistry. In the in vitro model, after adding pathway inhibitors, qPCR was used to detect the expression of downstream genes. Broad-targeted metabolomics analysis was performed on the differential metabolites in the serum and enrichment was carried out, and important proteins were used to verify the mechanism.

RESULTS: Both in vitro and in vivo experiments confirmed AMB's significant chronic renal failure (CRF)-improving efficacy. RNA-seq combined with clinical databases revealed AMB protected injured MPC5 cells by downregulating IL-17 pathway genes (CXCL2, CXCL5, LCN2, CEBPβ, IL-6). The qPCR results showed that AMB exerted its therapeutic effect highly dependent on the IL-17 pathway and had a synergistic effect with C25-140. Serum metabolome results showed that AMB exerted its therapeutic effects by affecting glycerophospholipid metabolism and tryptophan metabolism. Immunohistochemistry validated changes in these target proteins.

CONCLUSIONS: AMB delays CRF by regulating the IL-17 pathway and affecting tryptophan metabolism and glycerophospholipid metabolism, providing a scientific basis for its clinical application.