Uncovering the pharmacological mechanisms of bifendate against chronic kidney disease using computational pharmacology and experimental verification.

Abstract

Chronic kidney disease (CKD) is a progressive ailment identified by renal fibrosis, inflammation, and mitochondrial dysfunction, necessitating the development of novel therapeutic interventions. Bifendate (dimethyl diphenyl bicarboxylate [DDB]), a known hepatoprotective agent, has shown promising antifibrotic properties, but its potential in CKD remains unexplored. This study integrates computational pharmacology, molecular docking, and experimental validation to explicate the mechanisms of renoprotection by DDB. Curative targets for CKD and DDB were identified from DisGeNET, GeneCards, and SwissTargetPrediction. Potential DDB targets against CKD were analyzed via STRING for protein interactions. Gene ontology and pathway enrichment (Database for Annotation, Visualization, and Integrated Discovery and Kyoto Encyclopedia of Genes and Genomes) were conducted, followed by network construction and analysis using Cytoscape (Institute for Systems Biology, USA). Network analysis identified 89 overlapping targets between DDB and CKD, including key regulators such as NF-κB1, PTGS2, and PPARG, which were enriched in multiple pathways, including calcium, Ras, ROS, NF-κB, and cAMP signaling. To validate these findings, a unilateral ureteral obstruction model in Sprague-Dawley rats was employed. DDB administration significantly mitigated kidney fibrosis, improved renal function markers, and preserved kidney morphology. Histological analyses confirmed that DDB attenuated tubular injury, glomerulosclerosis, and excessive collagen deposition. Furthermore, immunohistochemical assessments demonstrated that DDB suppressed epithelial-mesenchymal transition by restoring E-cadherin and reducing α-smooth muscle actin expression. Mitochondrial biogenesis was enhanced through PGC-1α upregulation, while inflammatory responses were dampened via NF-κB pathway inhibition. These findings highlight DDB's multifaceted therapeutic potential in CKD, acting through fibrosis inhibition, mitochondrial protection, and anti-inflammatory mechanisms. This study provides a strong foundation for further clinical investigations into DDB as a potential treatment for CKD, offering new insights into its mechanistic pathways. SIGNIFICANCE STATEMENT: This study demonstrates bifendate's therapeutic potential for chronic kidney disease through network pharmacology, identifying 89 common targets. Experimental validation in a unilateral ureteral obstruction model confirmed its renoprotective effects, revealing multi-target mechanisms against renal fibrosis and injury.