The kidney has robust and early inflammatory changes in response to challenges in caloric balance, from high fat feeding or with diabetes. Progressive accumulation of matrix molecules, largely driven by TGF-b, leads to ultimate organ dysfunction and renal failure. The global epidemic of obesity and diabetes is a major contributor to the worldwide increase in end-stage renal disease. A major theory to explain renal inflammation and fibrosis with diabetes has been the concept that enhanced mitochondrial-derived superoxide production plays a central role (1; 2), however this concept has not been proven in live animals. Using a DHE-based method to evaluate superoxide levels in organs in real time (3), we found that the normal kidney has a robust degree of superoxide production (4). Surprisingly, the kidneys from several models of diabetes (streptozotocin, Akita) have a marked reduction of renal superoxide levels in live animals. The reduction of renal superoxide was found in tissue sections and by electron paramagnetic resonance of kidney cortex. Mitochondrial production of hydrogen peroxide was also reduced in the diabetic kidney. The reduced superoxide production was associated with reduced activity of the electron chain complex and reduced mitochondrial biogenesis. The basis for reduction of reduced renal superoxide production, mitochondrial electron chain complex activity and mitochondrial biogenesis appears to be due to reduction of the master energy sensor, AMPK. A consequence of AMPK inhibition is an increase in inflammation and fibrosis mediated in part by NAPDH oxidases and TGF-b (4; 5). Stimulation of AMPK led to an increase in renal superoxide, complex activity and mitochondrial biogenesis. The increased superoxide levels was associated with a reduction of inflammation and matrix accumulation. The beneficial role of mitochondrial superoxide has been termed mitochondrial hormesis (6; 7). The concept of mitochondrial hormesis is consistent with data demonstrating that reduction of oxidant production is deleterious in several species and in humans (6). Mitochondrial hormesis also suggests that approaches to enhance mitochondrial function via activators of AMPK and PGC1a from exercise, caloric restriction, or medications will result in stimulation of mitochondrial superoxide production, reduce inflammation and fibrosis and ultimately promote organ healing.