Activation of the AMP-related kinase (AMPK) induces renal vasodilatation and downregulates Nox-derived reactive oxygen species (ROS) generation

AMPK, metabolism, and vascular function

“…and phosphorylation of the AMPK downstream target ACC, thus supporting the specificity of A7669662 vascular action and linking AMPK vasoactive and metabolic actions in the arterial wall[65,66,98,99]. New synthetic compounds such as MT63-78 and PF-249 interact with the allosteric drug and metabolite (ADaM) site located between AMPK α and β subunits and allosterically activate both β 1-and β 2 -containing AMPK trimers[100,101]; concerning cardiovascular protective therapeutic potential of these agents, cardiac hypertrophy and glycogen accumulation have been reported as offside target effects[101].…”

“…However, other studies have contradictorily shown that activators of AMPK (AICAR and A769662) inhibit EDH-like relaxations, through blocking preferentially small conductance Ca 2+ -activated K + (K Ca ) channels in mesenteric arteries [108]. In a recent study, our group first demonstrated that AMPK activation in kidney resistance arteries induced a potent renal vasodilation through endothelium-dependent mechanisms involving activation of both eNOS by eNOS Ser 1177 phosphorylation concomitant with increased Thr 172 pAMPK, and endothelial intermediate-conductance calcium-activated K + channels, the latter inducing hyperpolarization of ECs that further spreads through myoendothelial gap junctions to the underlying VSM to reduce calcium and induce relaxation [99,116], as shown in Fig. 2.…”

“…Further studies are needed to elucidate the mechanisms underlying the vascular actions of these new agents. Ser 633 , as depicted from the increased eNOS Ser 1177 and/or Ser 633 phosphorylation concomitant with increased Thr 172 pAMPK and AMPK activity found in human ECs or intact arteries in response to various stimuli including shear stress, adiponectin, or pharmacological activators[58][59][60][61]99]; (b) suppression of GTP-cyclohydrolase I (GTPCH) degradation and the subsequent increase in tetrahydrobiopterin (BH4) levels, supported by the reduced levels of GTPCH I and BH4 in aortas from the AMPKα 2 (−/−) mice [105]; (c) increase in heat-shock protein 90 (Hsp90) association with eNOS, as demonstrated by the augmented eNOS Ser 1179 phosphorylation, NO bioactivity, and coimmunoprecipitation of eNOS with hsp90 induced by AICAR and metformin in wild-type C57BL6 mice but not in AMPKα 1 knockout mice…”

Diabetes Mellitus and Cardiovascular Diseases: Nutraceutical Interventions Related to Caloric Restriction

“…In addition, it has recently been demonstrated by García-Prieto et al that Ca 2+ /calmodulindependent kinase II plays a crucial action in mediating CR-induced AMPK activation through H2O2 increase in aortas from obese rats [58]. In addition, AMPK improves NO bioavailability by downregulating NOX4 expression, as demonstrated by studies using different drugs able to active AMPK [59]. For instance, Hasan et al have recently demonstrated that canagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor used in T2DM treatment, ameliorates a cardiac oxidative microenvironment by AMPK/NOX4 signaling [60].…”

Early Diabetes Aggravates Renal Ischemia/reperfusion-induced Acute Kidney Injury 

“…Then, the protein samples were transferred to polyvinylidene uoride (PVDF) membranes (GE Healthcare Life Sciences). The membranes were incubated with primary antibodies against autophagic markers [rabbit anti-AMPKα (1:1000, Cell Signaling, Danvers, MA, USA [25]), phospho-AMPKα (1:1000, Cell Signaling [26]) rabbit anti-Beclin-1 (1:1000, Cell Signaling [27]), rabbit anti-LC3 I and II (1:1000, Cell Signaling [28]), rabbit anti-SQSTM1/p62 (1:1000, Cell Signaling [29])] and mouse anti-β-actin (1:8000, Abcam, Cambridge, MA, UK) and then incubated with conjugated secondary antibodies. Then, the membranes were exposed to the reagent for immunodetection with ECLTM luminescence (Amersham, GE) and subsequently to a photodocumenter (Amersham Imager 600, GE).…”