Beneficial Effects of AMP-Activated Protein Kinase Agonists in Kidney Ischemia-Reperfusion: Autophagy and Cellular Stress Markers

The ultrasensitive energy sensor AMP-activated protein kinase (AMPK) orchestrates the regulation of energy-generating and energy-consuming pathways. AMPK is highly expressed in the kidney where it is reported to be involved in a variety of physiological and pathological processes including ion transport, podocyte function, and diabetic renal hypertrophy. Sodium transport is the major energy-consuming process in the kidney, and AMPK has been proposed to contribute to the coupling of ion transport with cellular energy metabolism. Specifically, AMPK has been identified as a regulator of several ion transporters of significance in renal physiology, including the cystic fibrosis transmembrane conductance regulator (CFTR), the epithelial sodium channel (ENaC), the Na+-K+-2Cl− cotransporter (NKCC), and the vacuolar H+-ATPase (V-ATPase). Identified regulators of AMPK in the kidney include dietary salt, diabetes, adiponectin, and ischemia. Activation of AMPK in response to adiponectin is described in podocytes, where it reduces albuminuria, and in tubular cells, where it reduces glycogen accumulation. Reduced AMPK activity in the diabetic kidney is associated with renal accumulation of triglyceride and glycogen and the pathogenesis of diabetic renal hypertrophy. Acute renal ischemia causes a rapid and powerful activation of AMPK, but the functional significance of this observation remains unclear. Despite the recent advances, there remain significant gaps in the present understanding of both the upstream regulating pathways and the downstream substrates for AMPK in the kidney. A more complete understanding of the AMPK pathway in the kidney offers potential for improved therapies for several renal diseases including diabetic nephropathy, polycystic kidney disease, and ischemia-reperfusion injury.

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Pentamethylquercetin generates beneficial effects in monosodium glutamate-induced obese mice and C2C12 myotubes by activating AMP-activated protein kinase

Diabetologia ◽

10.1007/s00125-012-2519-z ◽

2012 ◽

Vol 55 (6) ◽

pp. 1836-1846 ◽

Cited By ~ 26

Author(s):

J. Z. Shen ◽

L. N. Ma ◽

Y. Han ◽

J. X. Liu ◽

W. Q. Yang ◽

...

Keyword(s):

Protein Kinase ◽

Monosodium Glutamate ◽

C2c12 Myotubes ◽

Obese Mice ◽

Beneficial Effects ◽

Amp Activated Protein Kinase

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AMP-activated protein kinase pathway: a potential therapeutic target in cardiometabolic disease

Clinical Science ◽

10.1042/cs20080066 ◽

2009 ◽

Vol 116 (8) ◽

pp. 607-620 ◽

Cited By ~ 109

Author(s):

Aaron K. F. Wong ◽

Jacqueline Howie ◽

John R. Petrie ◽

Chim C. Lang

Keyword(s):

Protein Kinase ◽

Metabolic Diseases ◽

Elongation Factor ◽

Cardiometabolic Disease ◽

Acid Oxidation ◽

Ampk Activation ◽

Atp Production ◽

Beneficial Effects ◽

Eukaryotic Elongation Factor ◽

Amp Activated Protein Kinase

AMPK (AMP-activated protein kinase) is a heterotrimetric enzyme that is expressed in many tissues, including the heart and vasculature, and plays a central role in the regulation of energy homoeostasis. It is activated in response to stresses that lead to an increase in the cellular AMP/ATP ratio caused either by inhibition of ATP production (i.e. anoxia or ischaemia) or by accelerating ATP consumption (i.e. muscle contraction or fasting). In the heart, AMPK activity increases during ischaemia and functions to sustain ATP, cardiac function and myocardial viability. There is increasing evidence that AMPK is implicated in the pathophysiology of cardiovascular and metabolic diseases. A principle mode of AMPK activation is phosphorylation by upstream kinases [e.g. LKB1 and CaMK (Ca2+/calmodulin-dependent protein kinase], which leads to direct effects on tissues and phosphorylation of various downstream kinases [e.g. eEF2 (eukaryotic elongation factor 2) kinase and p70 S6 kinase]. These upstream and downstream kinases of AMPK have fundamental roles in glucose metabolism, fatty acid oxidation, protein synthesis and tumour suppression; consequently, they have been implicated in cardiac ischaemia, arrhythmias and hypertrophy. Recent mechanistic studies have shown that AMPK has an important role in the mechanism of action of MF (metformin), TDZs (thiazolinediones) and statins. Increased understanding of the beneficial effects of AMPK activation provides the rationale for targeting AMPK in the development of new therapeutic strategies for cardiometabolic disease.

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Beneficial effects of β-sitosterol on glucose and lipid metabolism in L6 myotube cells are mediated by AMP-activated protein kinase

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2008.10.136 ◽

2008 ◽

Vol 377 (4) ◽

pp. 1253-1258 ◽

Cited By ~ 35

Author(s):

Seung-Lark Hwang ◽

Ha-Na Kim ◽

Hyun-Hee Jung ◽

Ji-Eun Kim ◽

Dong-Kyu Choi ◽

...

Keyword(s):

Lipid Metabolism ◽

Protein Kinase ◽

Beneficial Effects ◽

Glucose And Lipid Metabolism ◽

Amp Activated Protein Kinase

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Isoform-selective 5′-AMP-activated protein kinase-dependent preconditioning mechanisms to prevent postischemic leukocyte-endothelial cell adhesive interactions

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00944.2010 ◽

2011 ◽

Vol 300 (4) ◽

pp. H1352-H1360 ◽

Cited By ~ 19

Author(s):

F. Spencer Gaskin ◽

Kazuhiro Kamada ◽

Mozow (Yusof) Zuidema ◽

Allan W. Jones ◽

Leona J. Rubin ◽

...

Keyword(s):

Nitric Oxide ◽

Endothelial Cell ◽

Protein Kinase ◽

Endothelial Nitric Oxide Synthase ◽

Ischemia Reperfusion ◽

Cell Adhesive ◽

Adhesive Interactions ◽

Amp Activated Protein Kinase ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

We previously demonstrated that preconditioning induced by ethanol consumption at low levels [ethanol preconditioning (EPC)] or with 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside (AICAR-PC) 24 h before ischemia-reperfusion prevents postischemic leukocyte-endothelial cell adhesive interactions (LEI) by a mechanism that is initiated by nitric oxide formed by endothelial nitric oxide synthase. Recent work indicates that 1) ethanol increases the activity of AMP-activated protein kinase (AMPK) and 2) AMPK phosphorylates endothelial nitric oxide synthase at the same activation site seen following EPC (Ser1177). In light of these observations, we postulated that the heterotrimeric serine/threonine kinase, AMPK, may play a role in triggering the development of the anti-inflammatory phenotype induced by EPC. Ethanol was administered to C57BL/6J mice by gavage in the presence or absence of AMPK inhibition. Twenty-four hours later, the numbers of rolling and adherent leukocytes in postcapillary venules of the small intestine were recorded using an intravital microscopic approach. Following 45 min of ischemia, LEI were recorded after 30 and 60 min of reperfusion or at equivalent time points in control animals. Ischemia-reperfusion induced a marked increase in LEI relative to sham-operated control mice. The increase in LEI was prevented by EPC, an effect that was lost with AMPK inhibition during the period of ethanol exposure. Studies conducted in AMPK α1- and α2-knockout mice suggest that the anti-inflammatory effects of AICAR are not dependent on which isoform of the catalytic α-subunit is present because a deficiency of either isoform results in a loss of protection. In sharp contrast, EPC appears to be triggered by an AMPK α2-isoform-dependent mechanism.

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