br The role of AMPK beyond energy homeostasis

The role of AMPK beyond MRS1523 homeostasis: regulating metabolism AMPK plays a major role in glucose homeostasis by modulating glucose transport in peripheral tissues [20]. Skeletal muscle, one of the main peripheral tissues involved in glucose uptake and disposal, expresses glucose transporter type 4 (GLUT4). In hyperglycemia, insulin promotes the translocation of intracellular vesicular GLUT4 to the cell membrane, thereby increasing glucose uptake in the muscle [6]. AMPK activation contributes to glucose transport in a similar way as insulin. The result is AMPK-induced glucose uptake stimulation in skeletal cells, with increased expression of enzymes specialized in glucose uptake such as GLUT4 and hexokinase II [6]. Moreover, AMPK directly phosphorylates the GLUT4 enhancer factor that is essential in the regulation of GLUT4 expression. Hexokinase phosphorylates glucose entering the cell, allowing for a structural change that prevents glucose from leaving the cell in the first step of glycolysis. Overall, these sequential alterations in the expression of enzymes involved in glucose uptake are the ultimate result of AMPK activation, which stimulates catabolic processes that counter the deleterious effects of glucose excess and maintains energy homeostasis. Hyperglycemia is a causative factor in the development of DN through its detrimental effects on glomerular and mesangial cells. Some in vitro studies have demonstrated its association with mesangial cell proliferation and hypertrophy, along with increased matrix production and basement membrane thickening [21]. Moreover, hyperglycemia-induced upregulation of vascular endothelial growth factor expression in podocytes increases vascular permeability [21]. In addition to these changes, classical pathways involving the production of advanced glycosylation end products, activation of protein kinase C, and reinforcement of the aldose reductase pathway contribute to the development of DN, in which oxidative stress appears to be a common theme [22,23]. In this regard, targeting AMPK in DN could ameliorate these adverse effects by regulating glucose-induced oxidative stress metabolism [4]. There is growing evidence regarding the role of AMPK in mediating intracellular signaling pathways, that is, the alteration of cellular redox state and antioxidant enzyme expression via the AMPK transcriptional activity of class O forkhead box (FoxO) signaling pathway [23]. FoxO proteins are an evolutionary conserved subfamily of transcriptional factors involved in the regulation of energy metabolism. In detail, it increases the expression of antioxidant enzymes, promotes mitochondrial biogenesis, cell survival, and longevity in several tissues, and even participates in tumor suppression [22]. The transcriptional activity of FoxO3a, one of the 4 members of the family consisting of FoxO1, FoxO3, FoxO4, and FoxO6, is further modulated by AMPK in response to metabolic stress. Moreover, FoxO3a is known to shield quiescent cells from reactive oxygen species (ROS) by antagonizing apoptosis through which oxidative stress is reduced by directly increasing their quantities of manganese superoxide dismutase (SOD) messenger RNA and protein [21]. It is well known that the activity of autophatic process is closely related to changes in the production of ROS. Although mild oxidative stress-induced autophagic process is beneficial for cell survival, excessive oxidative damage caused by high ROS would bypass autophagy induction and evoke apoptosis or necrosis, leading to promote cell death [24]. Antioxidant enzymes, including thioredoxin, peroxiredoxin, Mn-SOD, and catalase, are found to be upregulated on activation of the AMPK–FoxO3a signaling pathway [25]. Therefore, on ROS exposure, AMPK, silent information regulator T1 (SIRT1), a well-known FoxO3a coactivator [26], and FoxO3a are expected to intertwine closely to regulate the apoptotic and autophagy crosstalk [22].