Empagliflozin causes nephrotoxicity in patients on guideline-directed medical therapy via urokinase-type plasminogen activator: An in silico approach

Guideline-directed medical therapy (GDMT) has been the standard pharmacotherapy for the treatment of HFrEF patients. However, these drugs cause severe side effects like nephrotoxicity. Empagliflozin being a SGLT2 inhibitor has been recently introduced in GDMT, and causes nephrotoxicity to patients. Although, the mechanism how it causes nephrotoxicity is not known. Hence, in the present study, we aimed to utilize system biology tools to predict the potential proteins and pathways responsible for nephrotoxicity. In the present study, we performed network analysis to predict the potential proteins, gene ontology analysis predicted the major cellular components, molecular function and biological process, and molecular docking was performed on empagliflozin with the identified hub genes followed by its validation using molecular dynamic simulations. Network analysis revealed CD44, EGFR, LEP, PLAU, TNFRSF1A, and ATM to be the potential proteins being modulated via nuclear factor-kappa B signalling pathway. Molecular docking revealed the empagliflozin-PLAU complex to possess the highest binding affinity of - 8.0 kcal/ mol with three hydrogen bond interactions with residues GLN192, ASP194, and SER195. In addition, molecular dynamic simulation studies revealed the empagliflozin-PLAU complex to be stable throughout the MD run with 3-4 consistent hydrogen bonds. Hence, the present study concludes that empagliflozin causes nephrotoxicity in heart failure patients via urokinase-type plasminogen activator by regulating the NF -kappa B signalling pathway.