Mechanism exploration of Wenshen Jianpi Decoction on renoprotection in diabetic nephropathy via transcriptomics and metabolomics

• WSJPD could improve renal morphology and function, decrease inflammatory factors and oxidative stress markers in DN rats. • Transcriptomics discovered that 212 genes were up-regulated in the DN model group and down-regulated in the WSJPR group. Conversely, 80 genes were down-regulated in the DN model group and up-regulated in the WSJPD group. • 14 metabolites from rat serum samples were identified as candidate biomarkers. • WSJPR ameliorated renal damage in DN model rats by regulating kidney pyrimidine metabolism, inflammation-related pathways, and AGE-RAGE signaling pathway. • The potential renoprotective effects of WSJPD were verified by histopathology, ELISA, and qRT-PCR. Diabetic nephropathy (DN) is a severe chronic microvascular complications of diabetes mellitus and the leading cause of end-stage renal disease. Although many therapeutic approaches have been developed for treatment of DN, there is still a risk of disease progression. Wenshen Jianpi Decoction (WSJPD), a traditional Chinese medicine, have demonstrated considerable clinical efficacy in treating DN. However, the therapeutic mechanisms of WSJPD remain unclear. The study aimed to assess the potential anti-renal injury effects of WSJPD as well as the underlying mechanism. Network pharmacology was performed to predict the potential targets of WSJPD in DN. Subsequently, HE, PAS, Masson staining, TEM and ELISA were used to assess the effects of WSJPD on renal injury in DN rats. Transcriptomics, metabolomics, and qRT-PCR were employed to analyze the potential mechanism. Network pharmacology analysis revealed that WSJPD might exert a beneficial impact on renal inflammation via the AGE-RAGE signaling pathway. The results of animal experiments indicated that WSJPD had a renoprotective effect by renal dysfunction improvement, inflammation inhibition, glycogen accumulation and podocyte injury suppression.Transcriptomic measures discovered that 212 genes were up-regulated in the DN model group and down-regulated in the WSJPD group. Conversely, 80 genes were down-regulated in the DN model group and up-regulated in the WSJPD group. Moreover, 14 metabolites from rat serum samples were identified as candidate biomarkers. Further analysis demonstrated that WSJPD ameliorated the metabolic disorders and exerted a protective effect by up-regulation of uridine-mediated pyrimidine metabolism, inhibition of inflammation mediated by the NF-κB and TNF signaling pathways, and inhibition of oxidative stress and inflammation mediated by the AGE-RAGE signaling pathway. Our findings showed that WSJPD ameliorated renal damage in DN model rats by regulating kidney pyrimidine metabolism, inflammation-related pathways, and AGE-RAGE signaling pathway. The potential renoprotective effects were verified by histopathology, ELISA, and qRT-PCR. This study not only support a foundation for interpretation of the therapeutic effects of WSJPD on renal lesions, but also provide data support for further explorations of the novel compound preparations to improve renal function in DN.