Integrated analysis of comprehensive metabolomics and network pharmacology to reveal the mechanisms of abelmoschus manihot (L.) medik. in the treatment of cisplatin-induced chronic kidney disease.

Background: Abelmoschus manihot (L.) Medik ("Huangkui" in Chinese, HK) has been widely used for the treatment of kidney diseases. Nephrotoxicity is the side effect of cisplatin (CDDP), which greatly limits its clinical application. Therefore, CDDP could be used to establish the chronic kidney disease (CKD) model. However, the protective effects of HK on CDDP-induced CKD have not been investigated. Purpose: To explore the protective effect and underlying mechanisms of HK on multiple low-dose CDDP-induced CKD in rats by the integrated analysis of serum, kidney, and urine metabolomics and network pharmacology. Methods: The CKD model was induced by multiple low-dose CDDP. Body weight, organ index, serum biochemical, and kidney histology were examined to evaluate the effect of HK. Serum, kidney, and urine were collected and profiled by HILIC/RPLC-Q-TOF/MS-based metabolomics. Potential biomarkers (PBs) were screened according to the criteria of VIP >1, p < 0.01, and FC > 2, and then identified or assigned. The pathway analysis and PBs enrichment were conducted by MetaboAnalyst and ChemRICH. Furthermore, network pharmacology was adopted to dig out the active components and targets. Finally, the results from metabolomics and network pharmacology were integrated to confirm each other. Results: HK could recover the CDDP-induced abnormal pharmacological and metabolic profile changes. A total of 187 PBs were screened and identified from the serum, kidney, and urine metabolomics. Pathway analysis showed that multiple metabolic pathways, mainly related to amino acid and lipid metabolisms, were involved in the nephroprotective effect of HK, and especially, HK could significantly alleviate the disorder of tryptophan metabolism pathway in serum, kidney, and urine. Meanwhile, network pharmacology analysis revealed that 5 components in HK and 4 key genes could be responsible for the nephroprotection of HK, which also indicated that the metabolism of tryptophan played an important role in HK against CKD. Conclusion: HK has a nephroprotection on CDDP-induced CKD, mainly by restoring the dysregulation of tryptophan metabolism. Integrated analysis of serum, kidney, and urine metabolomics and network pharmacology was a powerful method for exploring pharmacological mechanisms and screening active components and targets of traditional Chinese medicine.