br New AMPK activators Fenofibrate is a

New AMPK activators Fenofibrate is a drug of the fibrate class used for the treatment of dyslipidemia [53] but is also an agent that could alleviate DN-induced alterations through AMPK activation (Fig. 2). Streptozotocin-induced diabetic rats treated with fenofibrate improved in not only renal functional parameters but also hyperglycemia-induced oxidative damage, as indicated by significantly increased levels of glutathione and catalase together with a noticeable decrease in lipid peroxidation. Fenofibrate's protective role in DN is in ameliorating endothelial dysfunction via increased modulation of AMPK, LKB1, and endothelial nitric oxide synthase (eNOS) expression [54]. In parallel with this, our previous experiments on the diabetic mouse model have demonstrated that fenofibrate can ameliorate albuminuria, glomerular matrix expansion, and inflammatory cell infiltration in the glomeruli and inhibit the accumulation of intrarenal free fatty acids and triglycerides. These results are compatible with the increased expression of PPARα and the activation of AMPK, PGC1α-ERR1α-pACC, as well as the suppression of SREBP-1c and carbohydrate regulatory element–binding protein-1, which constitutes the main downstream eletriptan hydrobromide in lipid metabolism. Fenofibrate decreased the phosphorylation of phosphatidylinositol-3 kinase-Akt and FoxO3a in the kidneys, resulting in the demonstrated BCL-2-to-BCL-2–associated X protein ratio and SOD1 levels. Such findings were reproducible in cultured mesangial cells as reflected by the prevention of high-glucose–induced apoptosis and oxidative stress via AMPK phosphorylation, PGC-1α-ERR-1α activation, and SREBP-1c and carbohydrate regulatory element–binding protein-1 suppression. Our results suggest that fenofibrate's potential as a therapeutic modality for DN lies in its ability to improve lipotoxicity by stimulating AMPK-PGC-1α-ERR-1α-FoxO3a signaling [55]. Anthocyanin, a flavonoid in the polyphenol class, is a major constituent of food color and has been reported to possess both antidiabetic and antioxidant properties [56]. As its beneficial effects on lipid metabolism are dependent on AMPK activation (Fig. 2) [57], we were prompted to investigate whether an anthocyanin-rich Seoritae extract could ameliorate DN in db/db mice. Indeed, anthocyanin ameliorated intrarenal lipid accumulation with attenuations of mesangial expansion and glomerular inflammation; these effects appear to be attributable to the increased phosphorylation of AMPK, activation of PPARα and peroxisome proliferator–activated receptor-gamma, and inhibitory activity of ACC and SREBP-1c, leading to a reduction in lipotoxicity in the kidney. In cultured human glomerular endothelial cells, anthocyanin prevented high-glucose–induced oxidative stress and apoptosis via activation of AMPK in the same manner. The results indicate that anthocyanin could help alleviate some of the pathologic features of DN as it prevents lipotoxicity-related apoptosis and oxidative stress in the diabetic kidney through the activation of AMPK and its downstream effectors [58]. Cinacalcet is a calcimimetic that positively modulates the calcium-sensing receptor (CaSR). It is mainly used in the treatment of secondary hyperparathyroidism in CKD patients as it both diminishes the inhibitory effect of parathyroid hormone on renal phosphate reabsorption and inhibits renal calcium excretion [59]. However, some recent reports have demonstrated that CaSRs are expressed in human endothelial cells and that their stimulation by cinacalcet induces nitric oxide (NO) production, resulting in vasorelaxation [60]. Moreover, calcimimetics significantly increased intracellular Ca++ levels, which in turn augmented NO release via a time- and Ca++-dependent increase in eNOS-ser1177 phosphorylation activity [61]. Based on these findings, we proposed that DN-induced endothelial dysfunction could be ameliorated by the activation of eNOS–NO as a result of cinacalcet administration (unpublished observations). Our preliminary work shows that cinacalcet reduced albuminuria without influencing either blood glucose or Ca++ concentration and ameliorated mesangial expansion and inflammatory cell infiltration in the glomerulus of db/db mice. In the renal cortex, cinacalcet increased the expression of CaSR and the phosphorylation of CaMKKβ and LKB1. Subsequent activation of AMPK was followed by the activation of PGC-1α and phospho-Ser1177 eNOS–NO (Fig. 2). In vitro studies were consistent with the fact that cinacalcet decreases oxidative stress and apoptosis; this effect is attributable to increases in intracellular Ca++ and the phosphorylation of CaMMKβ, LKB1, and AMPK. All these changes were associated with an increase in the phosphorylation of eNOS. Overall, our results suggest that cinacalcet increases intracellular Ca++, subsequently activating the CaMKKβ–LKB1–AMPK signaling pathway in the kidney. This increase and activation of relevant molecules ameliorates renal damage, potentially providing a therapeutic modality for DN.