Exploring the Therapeutic Potential of Plantaginis Herba in TreatingSalt-Sensitive Hypertension-Induced Renal Injury: Network PharmacologyAnalysis and Experimental Verification

INTRODUCTION: Plantaginis Herba (PH) is a traditional Chinese herb with broad pharmacological effects and has been used to treat hypertension. Salt-sensitive hypertension (SS-HT) is characterized by elevated blood pressure due to a high-salt diet and sodium intake. This study investigates the role and molecular mechanisms of PH in SS-HT-induced renal injury using network pharmacology and in vivo experiments. METHODS: The components of PH and potential therapeutic targets were identified through network pharmacology. The protein-protein interaction (PPI) network and Herb-CompoundsTargets-Disease-Pathway network were established. GO and KEGG enrichment analyses were performed using DAVID and bioinformatics tools. Active compounds were determined by ultraperformance liquid chromatography- tandem mass spectrometry (UPLC-MS/MS). A SS-HT model was established using male Dahl/SS rats given a high-salt diet, and then treated with lowand high-dose PH, as well as hydrochlorothiazide (HCTZ), upon which kidney injury, urine sodium metabolism-related factors, and PI3K/AKT/Nedd4-2/γ-ENaC pathway-related proteins levels were assessed using histopathological staining, ELISA, and Western blotting. RESULTS: Ninety-nine overlapping genes were identified between PH and SS-HT, with AKT1 highlighted as a hub target in the PPI network. The contents of dinatin, baicalin, baicalein, 6-OHluteolin, β-sitosterol, and stigmasterol in the PH extracts were 1.880, 2.973, 0.210, 1.797, 385.400, and 38.320 ng/mg, respectively. KEGG identified the PI3K-Akt signaling pathway as a core signaling pathway. In vivo experiments showed that PH could improve blood pressure and urinary sodium metabolism, ameliorate kidney histopathological injury, and inhibit apoptosis. Furthermore, PH increased p-PI3K/PI3K, p-AKT/AKT, and Nedd4-2 expression while inhibiting γ-ENaC expression, thereby improving kidney injury and sodium excretion function in SS-HT rats. DISCUSSION: PH contains multiple bioactive compounds and exerts its effects through multiple targets and pathways, effectively alleviating SS-HT and ameliorating pathological kidney damage, with an efficacy comparable to that of hydrochlorothiazide. PH improves urinary sodium metabolism and mitigates renal injury in SS-HT rats via the PI3K/AKT/Nedd4-2/γ-ENaC pathway. Although PH demonstrates potential as a therapeutic agent for SS-HT, the key functional components in PH and the mechanism by which Nedd4-2 participates in the degradation of γENaC remain to be further studied. CONCLUSION: PH ameliorates SS-HT-induced renal injury by regulating sodium metabolism and renal function, and by activating the PI3K/AKT/Nedd4-2/γ-ENaC pathway.