Blocking nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) and increasing the expression of adiponectin receptor-1 (AdipoR1) and AdipoR2 in renal tubular epithelial cells by AMPK activation and activating the AMPK-SIRT1-peroxisome proliferator-activated receptor (PPAR)-gamma coactivator (PGC)-1alpha axis and the peroxisome PPAR-alpha, reduced NOX4-derived intracellular ROS and lipotoxicity, and ameliorated OS, apoptosis and endothelial dysfunction in DN, which in turn reduced renal fibrosis and restored renal function. Here, NOX4 is linked to endothelial dysfunction.