Fig. 9.

Proposed mechanism through which spironolactone ameliorates endothelial dysfunction in the setting of chronic kidney disease; the mechanism involves inhibiting the activation of advanced glycation end products (AGE)/receptor for AGEs (RAGEs) axis. Spironolactone can inhibit the positive feedback loop of AGEs-induced RAGEs formation. Spironolactone can ameliorate endothelial dysfunction through a reversal of the downregulation of sirtuin-3 (SIRT3). SIRT3 can regulate mitochondrial oxidative stress. Reduced SIRT3 increases mitochondrial oxidative stress, which further increases the nicotinamide adenine dinucleotide phosphate oxidase (NOX-2) production, forming reactive oxygen species (ROS)-induced ROS release (RIRR).The overall increased oxidative stress ultimately results in endothelial dysfunction