Renoprotective effects of dapagliflozin and montelukast for diclofenac induced acute kidney injury through network pharmacology and experimental validation

Abstract Diclofenac (DIC)-prompted acute kidney injury (AKI) is associated with inflammation, oxidative stress, mitochondrial dysfunction, and dysregulated autophagy, all of which contribute to renal impairment. Using a network pharmacology approach followed by experimental validation, this study evaluated the reno-protecting actions of dapagliflozin (DAPA) and montelukast (MON) against DIC-induced AKI in rats, both alone and in combination. DisGeNET, GeneCards, and OMIM databases were used to identify AKI targets, whereas Swiss-Target-Prediction, Super-PRED, and SEA databases were used to identify expected DAPA and MON targets. Protein–protein interaction (PPI) network, gene ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment studies recognized significant pathways such as TNF-α, PI3K/AKT signalling, T-cell receptor signalling, microRNA regulation, and ROS. Experimental validation was conducted on thirty male SD rats, separated arbitrarily into five groups. A sole injection of DIC (100 mg/kg; i.p.) provoked AKI. Renal function markers, biomarkers for early kidney injury, oxidative stress, inflammatory mediators, indicators of mitochondrial biogenesis, and autophagy-related proteins were all evaluated. DIC resulted in significant renal dysfunction, oxidative stress, inflammation, mitochondrial impairment, DNA damage, and autophagy activation. While DAPA and MON alone partially mitigated these effects, their combination, even at lower doses of both drugs, provided greater renoprotection, most likely through multi-target regulation of inflammation, oxidative stress, and autophagy pathways. These findings emphasized that combining DAPA with MON allowed dose reduction of each agent, minimizing potential side effects while achieving superior renoprotection via managing inflammation, oxidative stress, and autophagy.