Exploring the mechanism of cardiorenal protection with finerenone based on network pharmacology

Large prospective trials have demonstrated that finerenone could reduce the risk of cardiovascular death and progression of renal failure among patients with chronic kidney disease (CKD) associated heart failure (HF) and/or type 2 diabetes mellitus (T2DM). The aim of this study was to explore the molecular mechanism of finerenone in the treatment of cardiorenal diseases through network pharmacology. The STITH, SwissTargetPrediction, PharmMapper, DrugBank and ChEMBL databases were used to screen the targets of finerenone. The diseases-related targets were retrieved from the DisGeNET, GeneCards, CTD, OMIM and MalaCards databases. The protein-protein interaction (PPI) network was conducted with STRING database and Cytoscape software. The clusterProfiler R package was used to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. The interactions of key targets and finerenone were analyzed by molecular docking in Autodock software. Diabetes mellitus was induced by intraperitoneal injection of streptozotocin. Histopathology of myocardial and renal tissues were observed by hematoxylin-eosin (HE) staining, and detection of protein expressions was conducted using western blotting. A total of 111 potential cardiorenal targets of finerenone were identified. The main mechanisms of action may be associated with lipid and atherosclerosis, fluid shear stress and atherosclerosis, AGE-RAGE signaling pathway in diabetic complications and diabetic cardiomyopathy. The hub targets demonstrated by the PPI network were CASP3, ALB, MMP9, EGFR, ANXA5, IGF1, SRC, TNFRSF1A, IL2 and PPARG, and the docking results suggested that finerenone could bind to these targets with high affinities. HE staining revealed the cardiorenal protection of finerenone on diabetic mice. In addition, the protein expressions of CASP3 and EGFR were increased while ALB was decreased in myocardial and renal tissues in diabetic mice compared with control mice, which were reversed by finerenone. This study suggested that finerenone exerts cardiorenal benefits through multiple targets and pathways.