(A) Diabetes results in decreased renal mitochondrial superoxide production, which is associated with decreased AMPK and PDH activity. Decreases in AMPK and PDH activity further reduce mitochondrial ROS production directly and through decreased PGC1α, which promotes decreased mitochondrial density, ultimately resulting in impaired renal podocyte function and albuminuria. Decreased AMPK also results in increased NADPH oxidase–dependent ROS production. (B) Restoration of renal mitochondrial ROS production by treatment with the AMPK activator AICAR reduces albuminuria and total renal oxidative stress. Mitochondrially derived ROS, which is stimulated by AICAR and amplified by a feedforward AMPK cascade, is protective in the setting of hyperglycemia. The failure of mitochondrial ROS generation contributes to diabetic kidney disease. Furthermore, AMPK activation reduces NADPH oxidase–dependent ROS formation.