Metformin s pluripotent roles are

Metformin's pluripotent roles are alluded to in terms of its antitumorigenic, glucose-lowering, and cardioprotective effects, which are due in part to its upregulation of AMPK activity [39,40]. Metformin's glucose-lowering effect is a result of reduced hepatic gluconeogenesis, whereas improved insulin sensitivity is mediated by the activation of the LKB1–AMPK axis [41]. It is suggested that metformin activates AMPK indirectly by inhibiting relevant cells from entering the mitochondrial respiratory chain, facilitating a switch from aerobic to anaerobic glycolysis in a manner that raises the cellular AMP-to-ATP ratio (Fig. 2) [42]. In addition, mounting evidence indicates that metformin-induced inactivation of mTOR by AMPK is associated with suppressed cell proliferation and increased autophagy, which are thought to lower cancer incidence [43]. Stimulation of AMPK activity with AICAR or metformin also resulted in inhibition of renal hypertrophy due in part to the prevention of glucose-induced protein synthesis. This was associated with decreases in the phosphorylation of Akt, mTOR, p70S6 kinase, and 4E-BP1 in renal cells, suggesting that AMPK regulates the initiation and elongation phases of translation [44]. Adiponectin, an adipose tissue-derived cytokine, is another AMPK activator. Decreases in the plasma level of adiponectin have been correlated with insulin resistance and obesity. In diabetes, reduced AMPK activity was noted to be associated with the renal accumulation of triglyceride and glycogen, which reflects the pathogenesis of diabetic renal hypertrophy [45]. Furthermore, adiponectin knockout mice exhibit increased albuminuria and fusion of the podocyte foot process [46]. In cultured podocytes, both adiponectin and AMPK activation reduced podocyte permeability to albumin, further ameliorating podocyte dysfunction. These effects are mostly due to the reduction of oxidative stress, with subsequent decreases in the level of nicotinamide fak pathway dinucleotide phosphate (NADPH) oxidase 4 in podocytes [46]. Another study showed that adiponectin receptor 1 and catalytic AMPK subunits α1 and α2 were localized to the glomeruli in endothelial, mesangial, podocyte, and parietal epithelial cells of Bowman capsule. The incubation of freshly isolated glomeruli with adiponectin led to the activation of AMPK via phosphorylation of its catalytic domain [47]. Resveratrol is a naturally occurring plant polyphenol that may target aging and obesity-related chronic diseases by preventing inflammation and oxidative stress [48]. It activates SIRT1, a nicotinamide adenine dinucleotide–dependent protein deacetylase, and AMPK (Fig. 2). Resveratrol's subsequent activation of downstream targets is expected to have some renoprotective effects involving changes in catabolic metabolism, mitochondrial activation, and angiogenesis, as well as enhanced cell survival [49–51]. Resveratrol's renoprotective effects with regard to oxidative stress and proinflammatory reactions are demonstrated in the attenuation of diabetes-induced superoxide anion, protein carbonyl levels, and cytokines interleukin-1β, tumor necrosis factor-α, and interleukin-6, which are associated with increased AMPK phosphorylation in diabetic renal tissues [52]. Moreover, in our previous experiment, db/db mice treated with resveratrol demonstrated improvements in not only renal functional parameters but also pathologic features. This manifestation was consistent with increases in the phosphorylation of AMPK, activation of SIRT1–PGC-1α signaling, and activation of the key downstream effector, PPARα–estrogen-related receptor (ERR)-1α–SREBP-1c. In addition, resveratrol reduced the activity of phosphatidylinositol-3 kinase-Akt phosphorylation and FoxO3a phosphorylation, which further caused a decrease in B-cell leukemia/lymphoma 2 (BCL-2)–associated X protein and increases in BCL-2, SOD1 and SOD2 production. In cultured mesangial cells, resveratrol attenuated renal apoptotic changes further, preventing high-glucose-induced oxidative stress and apoptosis through the phosphorylation of AMPK and activation of SIRT1--PGC-1α signaling and the downstream effector, PPARα--ERR-1α--SREBP1c. The results suggest that resveratrol prevents DN in db/db mice through the phosphorylation of AMPK and activation of SIRT1–PGC-1α signaling, which seem to prevent lipotoxicity-related apoptosis and oxidative stress in the kidney [8].