A New Prospect for the Treatment of Nephrotic Syndrome Based on Network Pharmacology Analysis

Abstract

Network pharmacology is an emerging field which is currently capturing interest in drug discovery and development. Chronic kidney conditions have become a threat globally due to its associated lifelong therapies. Nephrotic syndrome (NS) is a common glomerular disease that is seen in paediatric and adult population with characteristic manifestation of proteinuria, oedema, hypoalbuminemia, and hyperlipidemia. It involves podocyte damage with tubulointerstitial fibrosis and glomerulosclerosis. Till date there has been no specific treatment available for this condition that provides complete remission. Repurposing of drugs can thus be a potential strategy for the treatment of NS. Recently, epigenetic mechanisms were identified that promote progression of many renal diseases. Therefore, in the present study, we investigated two epigenetic drugs valproic acid (VPA) and all-trans retinoic acid (ATRA). Epigenetic drugs act by binging about changes in gene expression without altering the DNA sequence. The changes include DNA methylation or histone modifications. The targets for the two drugs ATRA and VPA were collated from ChEMBL and Binding DB. All the genes associated with NS were collected from DisGeNET and KEGG database. Interacting proteins for the target genes were acquired from STRING database. The genes were then subjected to gene ontology and pathway enrichment analysis using a functional enrichment software tool. A drug-target and drug-potential target-protein interaction network was constructed using the Cytoscape software. Our results revealed that the two drugs VPA and ATRA had 65 common targets that contributed to kidney diseases. Out of which, 25 targets were specifically NS associated. Further, our work exhibited that ATRA and VPA were synergistically involved in pathways of inflammation, renal fibrosis, glomerulosclerosis and possibly mitochondrial biogenesis and endoplasmic reticulum stress. We thus propose a synergistic potential of the two drugs for treating chronic kidney diseases, specifically NS. The outcomes will undoubtedly invigorate further preclinical and clinical explorative studies. We identify network pharmacology as an initial inherent approach in identifying drug candidates for repurposing and synergism.