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. The gene discussed is NOX4; the disease is renal fibrosis.