Ethnopharmacological relevance: The Chinese herbal Plantaginis Herba (PL) is one of the most widely used plants for both medicinal and dietary purposes. Plantaginis Herba is the main medicine used in a traditional Chinese prescription called Cheqiancao decoction, and it is known for its liver and kidney protective properties.

Aim of the study: The aim of the present study was to explore the interventions and mechanisms of PL in ADR nephropathy by performing an integrated analysis of in vitro and in vivo experiments.

Materials and methods: The ingredients of PL were analysed by Ultra High Performance Liquid Chromatography (UPLC). The biochemical indicators of renal injury in the serum and urine were detected by a Micronumerase assay and ELISA. The renal histopathology and ultrastructure were analysed by H&E staining, Masson's trichrome staining and transmission electron microscopy (TEM), respectively. By identifying the targets of PL and ADR nephropathy, a network of PL-constituents-targets-ADR nephropathy was constructed, and a KEGG signaling pathway enrichment analysis was performed to complete the network pharmacology. A transcriptomic analysis was performed on a sequencing platform (Illumina).

Results: Plantaginis Herba significantly decreased the levels of BUN, Scr, ALB, MAU and KIM-1. Plantaginis Herba inhibited renal histopathological injury and alleviate foot process fusion and podocyte basement membrane thickening. In addition, the results of the transcriptomic analysis and network pharmacology analysis indicated that the HIF-1, TGF-β, and PI3K/AKT signaling pathways; apoptosis; and ECM-receptor interactions might be pivotal pathways for the effect of the PL intervention on ADR nephropathy. Moreover, the validation results revealed that PL could effectively attenuate collagen fibre deposition and inhibit oxidative stress. Plantaginis Herba could regulate the expression levels of pivotal proteins in the β-catenin/TGF-β1, HIF-1, and PI3K signaling pathways in renal tissues. Plantaginis Herba could reduce the level of apoptosis and the percentage of decrease in the mitochondrial membrane potential (MMP) in primary renal cells from rats with ADR nephropathy, and regulate key proteins involved in mitochondrial apoptosis. Furthermore, Luteolin from PL had good affinity for HIF-1α, and the ability of Luteolin to ameliorate in ameliorating ADR-induced MPC-5 cell injury was attenuated by overexpressing HIF-1α.

Conclusions: Plantaginis Herba alleviates ADR-induced nephropathy by regulating mitochondrial apoptosis via the HIF-1α signaling pathway. Luteolin may be one of the active ingredients responsible for these effects, and these findings provide an innovative strategy for the intervention and treatment of ADR nephropathy.

Keywords: ADR nephropathy; HIF-1α signaling pathway; Mitochondrial apoptosis; Plantaginis Herba.

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