International Journal of Molecular Sciences

Editorial

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5 pages, 184 KiB

Open AccessEditorial

AMP-Activated Protein Kinase Signalling

by Dietbert Neumann and Benoit Viollet

Int. J. Mol. Sci. 2019, 20(3), 766; https://doi.org/10.3390/ijms20030766 - 12 Feb 2019

Cited by 7 | Viewed by 3889

Abstract

AMP-activated protein kinase (AMPK) regulates energy homeostasis in eukaryotic cells and organisms [...] Full article

(This article belongs to the Special Issue AMP-Activated Protein Kinase Signalling)

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Research

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17 pages, 2414 KiB

Open AccessArticle

A769662 Inhibits Insulin-Stimulated Akt Activation in Human Macrovascular Endothelial Cells Independent of AMP-Activated Protein Kinase

by Anastasiya Strembitska, Sarah J. Mancini, Jonathan M. Gamwell, Timothy M. Palmer, George S. Baillie and Ian P. Salt

Int. J. Mol. Sci. 2018, 19(12), 3886; https://doi.org/10.3390/ijms19123886 - 5 Dec 2018

Cited by 11 | Viewed by 6399

Abstract

Protein kinase B (Akt) is a key enzyme in the insulin signalling cascade, required for insulin-stimulated NO production in endothelial cells (ECs). Previous studies have suggested that AMP-activated protein kinase (AMPK) activation stimulates NO synthesis and enhances insulin-stimulated Akt activation, yet these studies [...] Read more.

Protein kinase B (Akt) is a key enzyme in the insulin signalling cascade, required for insulin-stimulated NO production in endothelial cells (ECs). Previous studies have suggested that AMP-activated protein kinase (AMPK) activation stimulates NO synthesis and enhances insulin-stimulated Akt activation, yet these studies have largely used indirect activators of AMPK. The effects of the allosteric AMPK activator A769662 on insulin signalling and endothelial function was therefore examined in cultured human macrovascular ECs. Surprisingly, A769662 inhibited insulin-stimulated NO synthesis and Akt phosphorylation in human ECs from umbilical veins (HUVECs) and aorta (HAECs). In contrast, the AMPK activators compound 991 and AICAR had no substantial inhibitory effect on insulin-stimulated Akt phosphorylation in ECs. Inhibition of AMPK with SBI-0206965 had no effect on the inhibition of insulin-stimulated Akt phosphorylation by A769662, suggesting the inhibitory action of A769662 is AMPK-independent. A769662 decreased IGF1-stimulated Akt phosphorylation yet had no effect on VEGF-stimulated Akt signalling in HUVECs, suggesting that A769662 attenuates early insulin/IGF1 signalling. The effects of A769662 on insulin-stimulated Akt phosphorylation were specific to human ECs, as no effect was observed in the human cancer cell lines HepG2 or HeLa, as well as in mouse embryonic fibroblasts (MEFs). A769662 inhibited insulin-stimulated Erk1/2 phosphorylation in HAECs and MEFs, an effect that was independent of AMPK in MEFs. Therefore, despite being a potent AMPK activator, A769662 has effects unlikely to be mediated by AMPK in human macrovascular ECs that reduce insulin sensitivity and eNOS activation. Full article

(This article belongs to the Special Issue AMP-Activated Protein Kinase Signalling)

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12 pages, 3154 KiB

Open AccessArticle

AMP-activated Protein Kinase Controls Immediate Early Genes Expression Following Synaptic Activation Through the PKA/CREB Pathway

by Sébastien Didier, Florent Sauvé, Manon Domise, Luc Buée, Claudia Marinangeli and Valérie Vingtdeux

Int. J. Mol. Sci. 2018, 19(12), 3716; https://doi.org/10.3390/ijms19123716 - 22 Nov 2018

Cited by 29 | Viewed by 6158

Abstract

Long-term memory formation depends on the expression of immediate early genes (IEGs). Their expression, which is induced by synaptic activation, is mainly regulated by the 3′,5′-cyclic AMP (cAMP)-dependent protein kinase/cAMP response element binding protein (cAMP-dependent protein kinase (PKA)/ cAMP response element binding (CREB)) [...] Read more.

Long-term memory formation depends on the expression of immediate early genes (IEGs). Their expression, which is induced by synaptic activation, is mainly regulated by the 3′,5′-cyclic AMP (cAMP)-dependent protein kinase/cAMP response element binding protein (cAMP-dependent protein kinase (PKA)/ cAMP response element binding (CREB)) signaling pathway. Synaptic activation being highly energy demanding, neurons must maintain their energetic homeostasis in order to successfully induce long-term memory formation. In this context, we previously demonstrated that the expression of IEGs required the activation of AMP-activated protein kinase (AMPK) to sustain the energetic requirements linked to synaptic transmission. Here, we sought to determine the molecular mechanisms by which AMPK regulates the expression of IEGs. To this end, we assessed the involvement of AMPK in the regulation of pathways involved in the expression of IEGs upon synaptic activation in differentiated primary neurons. Our data demonstrated that AMPK regulated IEGs transcription via the PKA/CREB pathway, which relied on the activity of the soluble adenylyl cyclase. Our data highlight the interplay between AMPK and PKA/CREB signaling pathways that allows synaptic activation to be transduced into the expression of IEGs, thus exemplifying how learning and memory mechanisms are under metabolic control. Full article

(This article belongs to the Special Issue AMP-Activated Protein Kinase Signalling)

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14 pages, 5854 KiB

Open AccessArticle

Loss of AMPKα2 Impairs Hedgehog-Driven Medulloblastoma Tumorigenesis

by Honglai Zhang, Rork Kuick, Sung-Soo Park, Claire Peabody, Justin Yoon, Ester Calvo Fernández, Junying Wang, Dafydd Thomas, Benoit Viollet, Ken Inoki, Sandra Camelo-Piragua and Jean-François Rual

Int. J. Mol. Sci. 2018, 19(11), 3287; https://doi.org/10.3390/ijms19113287 - 23 Oct 2018

Cited by 6 | Viewed by 4038

Abstract

The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that has a dual role in cancer, i.e., pro- or anti-tumorigenic, depending on the context. In medulloblastoma, the most frequent malignant pediatric brain tumor, several in vitro studies previously showed that [...] Read more.

The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that has a dual role in cancer, i.e., pro- or anti-tumorigenic, depending on the context. In medulloblastoma, the most frequent malignant pediatric brain tumor, several in vitro studies previously showed that AMPK suppresses tumor cell growth. The role of AMPK in this disease context remains to be tested in vivo. Here, we investigate loss of AMPKα2 in a genetically engineered mouse model of sonic hedgehog (SHH)-medulloblastoma. In contrast to previous reports, our study reveals that AMPKα2 KO impairs SHH medulloblastoma tumorigenesis. Moreover, we performed complementary molecular and genomic analyses that support the hypothesis of a pro-tumorigenic SHH/AMPK/CNBP axis in medulloblastoma. In conclusion, our observations further underline the context-dependent role of AMPK in cancer, and caution is warranted for the previously proposed hypothesis that AMPK agonists may have therapeutic benefits in medulloblastoma patients. Note: an abstract describing the project was previously submitted to the American Society for Investigative Pathology PISA 2018 conference and appears in The American Journal of Pathology (Volume 188, Issue 10, October 2018, Page 2433). Full article

(This article belongs to the Special Issue AMP-Activated Protein Kinase Signalling)

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13 pages, 2230 KiB

Open AccessArticle

AMPK Mediates Muscle Mass Change But Not the Transition of Myosin Heavy Chain Isoforms during Unloading and Reloading of Skeletal Muscles in Mice

by Tatsuro Egawa, Yoshitaka Ohno, Ayumi Goto, Shingo Yokoyama, Tatsuya Hayashi and Katsumasa Goto

Int. J. Mol. Sci. 2018, 19(10), 2954; https://doi.org/10.3390/ijms19102954 - 27 Sep 2018

Cited by 14 | Viewed by 4545

Abstract

5′AMP-activated protein kinase (AMPK) plays an important role in the regulation of skeletal muscle mass and fiber-type distribution. However, it is unclear whether AMPK is involved in muscle mass change or transition of myosin heavy chain (MyHC) isoforms in response to unloading or [...] Read more.

5′AMP-activated protein kinase (AMPK) plays an important role in the regulation of skeletal muscle mass and fiber-type distribution. However, it is unclear whether AMPK is involved in muscle mass change or transition of myosin heavy chain (MyHC) isoforms in response to unloading or increased loading. Here, we checked whether AMPK controls muscle mass change and transition of MyHC isoforms during unloading and reloading using mice expressing a skeletal-muscle-specific dominant-negative AMPKα1 (AMPK-DN). Fourteen days of hindlimb unloading reduced the soleus muscle weight in wild-type and AMPK-DN mice, but reduction in the muscle mass was partly attenuated in AMPK-DN mice. There was no difference in the regrown muscle weight between the mice after 7 days of reloading, and there was concomitantly reduced AMPKα2 activity, however it was higher in AMPK-DN mice after 14 days reloading. No difference was observed between the mice in relation to the levels of slow-type MyHC I, fast-type MyHC IIa/x, and MyHC IIb isoforms following unloading and reloading. The levels of 72-kDa heat-shock protein, which preserves muscle mass, increased in AMPK-DN-mice. Our results indicate that AMPK mediates the progress of atrophy during unloading and regrowth of atrophied muscles following reloading, but it does not influence the transition of MyHC isoforms. Full article

(This article belongs to the Special Issue AMP-Activated Protein Kinase Signalling)

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14 pages, 2453 KiB

Open AccessArticle

AMPK Activation Reduces Hepatic Lipid Content by Increasing Fat Oxidation In Vivo

by Marc Foretz, Patrick C. Even and Benoit Viollet

Int. J. Mol. Sci. 2018, 19(9), 2826; https://doi.org/10.3390/ijms19092826 - 19 Sep 2018

Cited by 112 | Viewed by 8713

Abstract

The energy sensor AMP-activated protein kinase (AMPK) is a key player in the control of energy metabolism. AMPK regulates hepatic lipid metabolism through the phosphorylation of its well-recognized downstream target acetyl CoA carboxylase (ACC). Although AMPK activation is proposed to lower hepatic triglyceride [...] Read more.

The energy sensor AMP-activated protein kinase (AMPK) is a key player in the control of energy metabolism. AMPK regulates hepatic lipid metabolism through the phosphorylation of its well-recognized downstream target acetyl CoA carboxylase (ACC). Although AMPK activation is proposed to lower hepatic triglyceride (TG) content via the inhibition of ACC to cause inhibition of de novo lipogenesis and stimulation of fatty acid oxidation (FAO), its contribution to the inhibition of FAO in vivo has been recently questioned. We generated a mouse model of AMPK activation specifically in the liver, achieved by expression of a constitutively active AMPK using adenoviral delivery. Indirect calorimetry studies revealed that liver-specific AMPK activation is sufficient to induce a reduction in the respiratory exchange ratio and an increase in FAO rates in vivo. This led to a more rapid metabolic switch from carbohydrate to lipid oxidation during the transition from fed to fasting. Finally, mice with chronic AMPK activation in the liver display high fat oxidation capacity evidenced by increased [C¹⁴]-palmitate oxidation and ketone body production leading to reduced hepatic TG content and body adiposity. Our findings suggest a role for hepatic AMPK in the remodeling of lipid metabolism between the liver and adipose tissue. Full article

(This article belongs to the Special Issue AMP-Activated Protein Kinase Signalling)

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15 pages, 2630 KiB

Open AccessArticle

Endothelial AMP-Activated Kinase α1 Phosphorylates eNOS on Thr495 and Decreases Endothelial NO Formation

by Nina Zippel, Annemarieke E. Loot, Heike Stingl, Voahanginirina Randriamboavonjy, Ingrid Fleming and Beate Fisslthaler

Int. J. Mol. Sci. 2018, 19(9), 2753; https://doi.org/10.3390/ijms19092753 - 13 Sep 2018

Cited by 20 | Viewed by 5618

Abstract

AMP-activated protein kinase (AMPK) is frequently reported to phosphorylate Ser1177 of the endothelial nitric-oxide synthase (eNOS), and therefore, is linked with a relaxing effect. However, previous studies failed to consistently demonstrate a major role for AMPK on eNOS-dependent relaxation. As AMPK also phosphorylates [...] Read more.

AMP-activated protein kinase (AMPK) is frequently reported to phosphorylate Ser1177 of the endothelial nitric-oxide synthase (eNOS), and therefore, is linked with a relaxing effect. However, previous studies failed to consistently demonstrate a major role for AMPK on eNOS-dependent relaxation. As AMPK also phosphorylates eNOS on the inhibitory Thr495 site, this study aimed to determine the role of AMPKα1 and α2 subunits in the regulation of NO-mediated vascular relaxation. Vascular reactivity to phenylephrine and acetylcholine was assessed in aortic and carotid artery segments from mice with global (AMPKα^−/−) or endothelial-specific deletion (AMPKα^ΔEC) of the AMPKα subunits. In control and AMPKα1-depleted human umbilical vein endothelial cells, eNOS phosphorylation on Ser1177 and Thr495 was assessed after AMPK activation with thiopental or ionomycin. Global deletion of the AMPKα1 or α2 subunit in mice did not affect vascular reactivity. The endothelial-specific deletion of the AMPKα1 subunit attenuated phenylephrine-mediated contraction in an eNOS- and endothelium-dependent manner. In in vitro studies, activation of AMPK did not alter the phosphorylation of eNOS on Ser1177, but increased its phosphorylation on Thr495. Depletion of AMPKα1 in cultured human endothelial cells decreased Thr495 phosphorylation without affecting Ser1177 phosphorylation. The results of this study indicate that AMPKα1 targets the inhibitory phosphorylation Thr495 site in the calmodulin-binding domain of eNOS to attenuate basal NO production and phenylephrine-induced vasoconstriction. Full article

(This article belongs to the Special Issue AMP-Activated Protein Kinase Signalling)

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25 pages, 3259 KiB

Open AccessArticle

Co-Expression Network Analysis of AMPK and Autophagy Gene Products during Adipocyte Differentiation

by Mahmoud Ahmed, Jin Seok Hwang, Trang Huyen Lai, Sahib Zada, Huynh Quoc Nguyen, Trang Min Pham, Miyong Yun and Deok Ryong Kim

Int. J. Mol. Sci. 2018, 19(6), 1808; https://doi.org/10.3390/ijms19061808 - 19 Jun 2018

Cited by 8 | Viewed by 6257

Abstract

Autophagy is involved in the development and differentiation of many cell types. It is essential for the pre-adipocytes to respond to the differentiation stimuli and may contribute to reorganizing the intracellulum to adapt the morphological and metabolic demands. Although AMPK, an energy sensor, [...] Read more.

Autophagy is involved in the development and differentiation of many cell types. It is essential for the pre-adipocytes to respond to the differentiation stimuli and may contribute to reorganizing the intracellulum to adapt the morphological and metabolic demands. Although AMPK, an energy sensor, has been associated with autophagy in several cellular processes, how it connects to autophagy during the adipocyte differentiation remains to be investigated. Here, we studied the interaction between AMPK and autophagy gene products at the mRNA level during adipocyte differentiation using public-access datasets. We used the weighted-gene co-expression analysis to detect and validate multiple interconnected modules of co-expressed genes in a dataset of MDI-induced 3T3-L1 pre-adipocytes. These modules were found to be highly correlated with the differentiation course of the adipocytes. Several novel interactions between AMPK and autophagy gene products were identified. Together, it is possible that AMPK-autophagy interaction is temporally and locally modulated in response to the differentiation stimuli. Full article

(This article belongs to the Special Issue AMP-Activated Protein Kinase Signalling)

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11 pages, 6179 KiB

Open AccessArticle

Serum Is Not Necessary for Prior Pharmacological Activation of AMPK to Increase Insulin Sensitivity of Mouse Skeletal Muscle

by Nicolas O. Jørgensen, Jørgen F. P. Wojtaszewski and Rasmus Kjøbsted

Int. J. Mol. Sci. 2018, 19(4), 1201; https://doi.org/10.3390/ijms19041201 - 15 Apr 2018

Cited by 5 | Viewed by 4719

Abstract

Exercise, contraction, and pharmacological activation of AMP-activated protein kinase (AMPK) by 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) have all been shown to increase muscle insulin sensitivity for glucose uptake. Intriguingly, improvements in insulin sensitivity following contraction of isolated rat and mouse skeletal muscle and prior AICAR [...] Read more.

Exercise, contraction, and pharmacological activation of AMP-activated protein kinase (AMPK) by 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) have all been shown to increase muscle insulin sensitivity for glucose uptake. Intriguingly, improvements in insulin sensitivity following contraction of isolated rat and mouse skeletal muscle and prior AICAR stimulation of isolated rat skeletal muscle seem to depend on an unknown factor present in serum. One study recently questioned this requirement of a serum factor by showing serum-independency with muscle from old rats. Whether a serum factor is necessary for prior AICAR stimulation to increase insulin sensitivity of mouse skeletal muscle is not known. Therefore, we investigated the necessity of serum for this effect of AICAR in mouse skeletal muscle. We found that the ability of prior AICAR stimulation to improve insulin sensitivity of mouse skeletal muscle did not depend on the presence of serum during AICAR stimulation. Although prior AICAR stimulation did not enhance proximal insulin signaling, insulin-stimulated phosphorylation of Tre-2/BUB2/CDC16- domain family member 4 (TBC1D4) Ser711 was greater in prior AICAR-stimulated muscle compared to all other groups. These results imply that the presence of a serum factor is not necessary for prior AMPK activation by AICAR to enhance insulin sensitivity of mouse skeletal muscle. Full article

(This article belongs to the Special Issue AMP-Activated Protein Kinase Signalling)

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Review

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16 pages, 1927 KiB

Open AccessReview

AMPK: Regulation of Metabolic Dynamics in the Context of Autophagy

by Isaac Tamargo-Gómez and Guillermo Mariño

Int. J. Mol. Sci. 2018, 19(12), 3812; https://doi.org/10.3390/ijms19123812 - 29 Nov 2018

Cited by 204 | Viewed by 9504

Abstract

Eukaryotic cells have developed mechanisms that allow them to link growth and proliferation to the availability of energy and biomolecules. AMPK (adenosine monophosphate-activated protein kinase) is one of the most important molecular energy sensors in eukaryotic cells. AMPK activity is able to control [...] Read more.

Eukaryotic cells have developed mechanisms that allow them to link growth and proliferation to the availability of energy and biomolecules. AMPK (adenosine monophosphate-activated protein kinase) is one of the most important molecular energy sensors in eukaryotic cells. AMPK activity is able to control a wide variety of metabolic processes connecting cellular metabolism with energy availability. Autophagy is an evolutionarily conserved catabolic pathway whose activity provides energy and basic building blocks for the synthesis of new biomolecules. Given the importance of autophagic degradation for energy production in situations of nutrient scarcity, it seems logical that eukaryotic cells have developed multiple molecular links between AMPK signaling and autophagy regulation. In this review, we will discuss the importance of AMPK activity for diverse aspects of cellular metabolism, and how AMPK modulates autophagic degradation and adapts it to cellular energetic status. We will explain how AMPK-mediated signaling is mechanistically involved in autophagy regulation both through specific phosphorylation of autophagy-relevant proteins or by indirectly impacting in the activity of additional autophagy regulators. Full article

(This article belongs to the Special Issue AMP-Activated Protein Kinase Signalling)

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19 pages, 1278 KiB

Open AccessReview

AMP-Activated Protein Kinase as a Key Trigger for the Disuse-Induced Skeletal Muscle Remodeling

by Natalia A. Vilchinskaya, Igor I. Krivoi and Boris S. Shenkman

Int. J. Mol. Sci. 2018, 19(11), 3558; https://doi.org/10.3390/ijms19113558 - 12 Nov 2018

Cited by 37 | Viewed by 6530

Abstract

Molecular mechanisms that trigger disuse-induced postural muscle atrophy as well as myosin phenotype transformations are poorly studied. This review will summarize the impact of 5′ adenosine monophosphate -activated protein kinase (AMPK) activity on mammalian target of rapamycin complex 1 (mTORC1)-signaling, nuclear-cytoplasmic traffic of [...] Read more.

Molecular mechanisms that trigger disuse-induced postural muscle atrophy as well as myosin phenotype transformations are poorly studied. This review will summarize the impact of 5′ adenosine monophosphate -activated protein kinase (AMPK) activity on mammalian target of rapamycin complex 1 (mTORC1)-signaling, nuclear-cytoplasmic traffic of class IIa histone deacetylases (HDAC), and myosin heavy chain gene expression in mammalian postural muscles (mainly, soleus muscle) under disuse conditions, i.e., withdrawal of weight-bearing from ankle extensors. Based on the current literature and the authors’ own experimental data, the present review points out that AMPK plays a key role in the regulation of signaling pathways that determine metabolic, structural, and functional alternations in skeletal muscle fibers under disuse. Full article

(This article belongs to the Special Issue AMP-Activated Protein Kinase Signalling)

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19 pages, 288 KiB

Open AccessReview

Hypothalamic AMPK as a Mediator of Hormonal Regulation of Energy Balance

by Baile Wang and Kenneth King-Yip Cheng

Int. J. Mol. Sci. 2018, 19(11), 3552; https://doi.org/10.3390/ijms19113552 - 11 Nov 2018

Cited by 57 | Viewed by 8808

Abstract

As a cellular energy sensor and regulator, adenosine monophosphate (AMP)-activated protein kinase (AMPK) plays a pivotal role in the regulation of energy homeostasis in both the central nervous system (CNS) and peripheral organs. Activation of hypothalamic AMPK maintains energy balance by inducing appetite [...] Read more.

As a cellular energy sensor and regulator, adenosine monophosphate (AMP)-activated protein kinase (AMPK) plays a pivotal role in the regulation of energy homeostasis in both the central nervous system (CNS) and peripheral organs. Activation of hypothalamic AMPK maintains energy balance by inducing appetite to increase food intake and diminishing adaptive thermogenesis in adipose tissues to reduce energy expenditure in response to food deprivation. Numerous metabolic hormones, such as leptin, adiponectin, ghrelin and insulin, exert their energy regulatory effects through hypothalamic AMPK via integration with the neural circuits. Although activation of AMPK in peripheral tissues is able to promote fatty acid oxidation and insulin sensitivity, its chronic activation in the hypothalamus causes obesity by inducing hyperphagia in both humans and rodents. In this review, we discuss the role of hypothalamic AMPK in mediating hormonal regulation of feeding and adaptive thermogenesis, and summarize the diverse underlying mechanisms by which central AMPK maintains energy homeostasis. Full article

(This article belongs to the Special Issue AMP-Activated Protein Kinase Signalling)

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15 pages, 3676 KiB

Open AccessReview

Structure and Physiological Regulation of AMPK

by Yan Yan, X. Edward Zhou, H. Eric Xu and Karsten Melcher

Int. J. Mol. Sci. 2018, 19(11), 3534; https://doi.org/10.3390/ijms19113534 - 9 Nov 2018

Cited by 172 | Viewed by 16175

Abstract

Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a heterotrimeric αβγ complex that functions as a central regulator of energy homeostasis. Energy stress manifests as a drop in the ratio of adenosine triphosphate (ATP) to AMP/ADP, which activates AMPK’s kinase activity, allowing it to [...] Read more.

Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a heterotrimeric αβγ complex that functions as a central regulator of energy homeostasis. Energy stress manifests as a drop in the ratio of adenosine triphosphate (ATP) to AMP/ADP, which activates AMPK’s kinase activity, allowing it to upregulate ATP-generating catabolic pathways and to reduce energy-consuming catabolic pathways and cellular programs. AMPK senses the cellular energy state by competitive binding of the three adenine nucleotides AMP, ADP, and ATP to three sites in its γ subunit, each, which in turn modulates the activity of AMPK’s kinase domain in its α subunit. Our current understanding of adenine nucleotide binding and the mechanisms by which differential adenine nucleotide occupancies activate or inhibit AMPK activity has been largely informed by crystal structures of AMPK in different activity states. Here we provide an overview of AMPK structures, and how these structures, in combination with biochemical, biophysical, and mutational analyses provide insights into the mechanisms of adenine nucleotide binding and AMPK activity modulation. Full article

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26 pages, 2101 KiB

Open AccessReview

AMP-Activated Protein Kinase and Host Defense against Infection

by Prashanta Silwal, Jin Kyung Kim, Jae-Min Yuk and Eun-Kyeong Jo

Int. J. Mol. Sci. 2018, 19(11), 3495; https://doi.org/10.3390/ijms19113495 - 6 Nov 2018

Cited by 57 | Viewed by 8507

Abstract

5′-AMP-activated protein kinase (AMPK) plays diverse roles in various physiological and pathological conditions. AMPK is involved in energy metabolism, which is perturbed by infectious stimuli. Indeed, various pathogens modulate AMPK activity, which affects host defenses against infection. In some viral infections, including hepatitis [...] Read more.

5′-AMP-activated protein kinase (AMPK) plays diverse roles in various physiological and pathological conditions. AMPK is involved in energy metabolism, which is perturbed by infectious stimuli. Indeed, various pathogens modulate AMPK activity, which affects host defenses against infection. In some viral infections, including hepatitis B and C viral infections, AMPK activation is beneficial, but in others such as dengue virus, Ebola virus, and human cytomegaloviral infections, AMPK plays a detrimental role. AMPK-targeting agents or small molecules enhance the antiviral response and contribute to the control of microbial and parasitic infections. In addition, this review focuses on the double-edged role of AMPK in innate and adaptive immune responses to infection. Understanding how AMPK regulates host defenses will enable development of more effective host-directed therapeutic strategies against infectious diseases. Full article

(This article belongs to the Special Issue AMP-Activated Protein Kinase Signalling)

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22 pages, 619 KiB

Open AccessReview

AMP-Activated Protein Kinase (AMPK)-Dependent Regulation of Renal Transport

by Philipp Glosse and Michael Föller

Int. J. Mol. Sci. 2018, 19(11), 3481; https://doi.org/10.3390/ijms19113481 - 6 Nov 2018

Cited by 32 | Viewed by 9064

Abstract

AMP-activated kinase (AMPK) is a serine/threonine kinase that is expressed in most cells and activated by a high cellular AMP/ATP ratio (indicating energy deficiency) or by Ca²⁺. In general, AMPK turns on energy-generating pathways (e.g., glucose uptake, glycolysis, fatty acid oxidation) [...] Read more.

AMP-activated kinase (AMPK) is a serine/threonine kinase that is expressed in most cells and activated by a high cellular AMP/ATP ratio (indicating energy deficiency) or by Ca²⁺. In general, AMPK turns on energy-generating pathways (e.g., glucose uptake, glycolysis, fatty acid oxidation) and stops energy-consuming processes (e.g., lipogenesis, glycogenesis), thereby helping cells survive low energy states. The functional element of the kidney, the nephron, consists of the glomerulus, where the primary urine is filtered, and the proximal tubule, Henle’s loop, the distal tubule, and the collecting duct. In the tubular system of the kidney, the composition of primary urine is modified by the reabsorption and secretion of ions and molecules to yield final excreted urine. The underlying membrane transport processes are mainly energy-consuming (active transport) and in some cases passive. Since active transport accounts for a large part of the cell’s ATP demands, it is an important target for AMPK. Here, we review the AMPK-dependent regulation of membrane transport along nephron segments and discuss physiological and pathophysiological implications. Full article

(This article belongs to the Special Issue AMP-Activated Protein Kinase Signalling)

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20 pages, 994 KiB

Open AccessReview

Involvement of 5′AMP-Activated Protein Kinase (AMPK) in the Effects of Resveratrol on Liver Steatosis

by Jenifer Trepiana, Iñaki Milton-Laskibar, Saioa Gómez-Zorita, Itziar Eseberri, Marcela González, Alfredo Fernández-Quintela and María P. Portillo

Int. J. Mol. Sci. 2018, 19(11), 3473; https://doi.org/10.3390/ijms19113473 - 5 Nov 2018

Cited by 34 | Viewed by 8799

Abstract

This review focuses on the role of 5′AMP-activated protein kinase (AMPK) in the effects of resveratrol (RSV) and some RSV derivatives on hepatic steatosis. In vitro studies, performed in different hepatic cell models, have demonstrated that RSV is effective in preventing liver TG [...] Read more.

This review focuses on the role of 5′AMP-activated protein kinase (AMPK) in the effects of resveratrol (RSV) and some RSV derivatives on hepatic steatosis. In vitro studies, performed in different hepatic cell models, have demonstrated that RSV is effective in preventing liver TG accumulation by activating AMPK, due to its phosphorylation. These preventive effects have been confirmed in studies conducted in animal models, such as mice and rats, by administering the phenolic compound at the same time as the diet which induces TG accumulation in liver. The literature also includes studies focused on other type of models, such as animals showing alcohol-induced steatosis or even steatosis induced by administering chemical products. In addition to the preventive effects of RSV on hepatic steatosis, other studies have demonstrated that it can alleviate previously developed liver steatosis, thus its role as a therapeutic tool has been proposed. The implication of AMPK in the delipidating effects of RSV in in vivo models has also been demonstrated. Full article

(This article belongs to the Special Issue AMP-Activated Protein Kinase Signalling)

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18 pages, 772 KiB

Open AccessReview

Interactive Roles for AMPK and Glycogen from Cellular Energy Sensing to Exercise Metabolism

by Natalie R. Janzen, Jamie Whitfield and Nolan J. Hoffman

Int. J. Mol. Sci. 2018, 19(11), 3344; https://doi.org/10.3390/ijms19113344 - 26 Oct 2018

Cited by 63 | Viewed by 8523

Abstract

The AMP-activated protein kinase (AMPK) is a heterotrimeric complex with central roles in cellular energy sensing and the regulation of metabolism and exercise adaptations. AMPK regulatory β subunits contain a conserved carbohydrate-binding module (CBM) that binds glycogen, the major tissue storage form of [...] Read more.

The AMP-activated protein kinase (AMPK) is a heterotrimeric complex with central roles in cellular energy sensing and the regulation of metabolism and exercise adaptations. AMPK regulatory β subunits contain a conserved carbohydrate-binding module (CBM) that binds glycogen, the major tissue storage form of glucose. Research over the past two decades has revealed that the regulation of AMPK is impacted by glycogen availability, and glycogen storage dynamics are concurrently regulated by AMPK activity. This growing body of research has uncovered new evidence of physical and functional interactive roles for AMPK and glycogen ranging from cellular energy sensing to the regulation of whole-body metabolism and exercise-induced adaptations. In this review, we discuss recent advancements in the understanding of molecular, cellular, and physiological processes impacted by AMPK-glycogen interactions. In addition, we appraise how novel research technologies and experimental models will continue to expand the repertoire of biological processes known to be regulated by AMPK and glycogen. These multidisciplinary research advances will aid the discovery of novel pathways and regulatory mechanisms that are central to the AMPK signaling network, beneficial effects of exercise and maintenance of metabolic homeostasis in health and disease. Full article

(This article belongs to the Special Issue AMP-Activated Protein Kinase Signalling)

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13 pages, 600 KiB

Open AccessReview

Reciprocal Regulation of AMPK/SNF1 and Protein Acetylation

by Ales Vancura, Shreya Nagar, Pritpal Kaur, Pengli Bu, Madhura Bhagwat and Ivana Vancurova

Int. J. Mol. Sci. 2018, 19(11), 3314; https://doi.org/10.3390/ijms19113314 - 25 Oct 2018

Cited by 45 | Viewed by 10251

Abstract

Adenosine monophosphate (AMP)-activated protein kinase (AMPK) serves as an energy sensor and master regulator of metabolism. In general, AMPK inhibits anabolism to minimize energy consumption and activates catabolism to increase ATP production. One of the mechanisms employed by AMPK to regulate metabolism is [...] Read more.

Adenosine monophosphate (AMP)-activated protein kinase (AMPK) serves as an energy sensor and master regulator of metabolism. In general, AMPK inhibits anabolism to minimize energy consumption and activates catabolism to increase ATP production. One of the mechanisms employed by AMPK to regulate metabolism is protein acetylation. AMPK regulates protein acetylation by at least five distinct mechanisms. First, AMPK phosphorylates and inhibits acetyl-CoA carboxylase (ACC) and thus regulates acetyl-CoA homeostasis. Since acetyl-CoA is a substrate for all lysine acetyltransferases (KATs), AMPK affects the activity of KATs by regulating the cellular level of acetyl-CoA. Second, AMPK activates histone deacetylases (HDACs) sirtuins by increasing the cellular concentration of NAD⁺, a cofactor of sirtuins. Third, AMPK inhibits class I and II HDACs by upregulating hepatic synthesis of α-hydroxybutyrate, a natural inhibitor of HDACs. Fourth, AMPK induces translocation of HDACs 4 and 5 from the nucleus to the cytoplasm and thus increases histone acetylation in the nucleus. Fifth, AMPK directly phosphorylates and downregulates p300 KAT. On the other hand, protein acetylation regulates AMPK activity. Sirtuin SIRT1-mediated deacetylation of liver kinase B1 (LKB1), an upstream kinase of AMPK, activates LKB1 and AMPK. AMPK phosphorylates and inactivates ACC, thus increasing acetyl-CoA level and promoting LKB1 acetylation and inhibition. In yeast cells, acetylation of Sip2p, one of the regulatory β-subunits of the SNF1 complex, results in inhibition of SNF1. This results in activation of ACC and reduced cellular level of acetyl-CoA, which promotes deacetylation of Sip2p and activation of SNF1. Thus, in both yeast and mammalian cells, AMPK/SNF1 regulate protein acetylation and are themselves regulated by protein acetylation. Full article

(This article belongs to the Special Issue AMP-Activated Protein Kinase Signalling)

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24 pages, 2382 KiB

Open AccessReview

AMPK Function in Mammalian Spermatozoa

by David Martin-Hidalgo, Ana Hurtado de Llera, Violeta Calle-Guisado, Lauro Gonzalez-Fernandez, Luis Garcia-Marin and M. Julia Bragado

Int. J. Mol. Sci. 2018, 19(11), 3293; https://doi.org/10.3390/ijms19113293 - 23 Oct 2018

Cited by 58 | Viewed by 8054

Abstract

AMP-activated protein kinase AMPK regulates cellular energy by controlling metabolism through the inhibition of anabolic pathways and the simultaneous stimulation of catabolic pathways. Given its central regulator role in cell metabolism, AMPK activity and its regulation have been the focus of relevant investigations, [...] Read more.

AMP-activated protein kinase AMPK regulates cellular energy by controlling metabolism through the inhibition of anabolic pathways and the simultaneous stimulation of catabolic pathways. Given its central regulator role in cell metabolism, AMPK activity and its regulation have been the focus of relevant investigations, although only a few studies have focused on the AMPK function in the control of spermatozoa’s ability to fertilize. This review summarizes the known cellular roles of AMPK that have been identified in mammalian spermatozoa. The involvement of AMPK activity is described in terms of the main physiological functions of mature spermatozoa, particularly in the regulation of suitable sperm motility adapted to the fluctuating extracellular medium, maintenance of the integrity of sperm membranes, and the mitochondrial membrane potential. In addition, the intracellular signaling pathways leading to AMPK activation in mammalian spermatozoa are reviewed. We also discuss the role of AMPK in assisted reproduction techniques, particularly during semen cryopreservation and preservation (at 17 °C). Finally, we reinforce the idea of AMPK as a key signaling kinase in spermatozoa that acts as an essential linker/bridge between metabolism energy and sperm’s ability to fertilize. Full article

(This article belongs to the Special Issue AMP-Activated Protein Kinase Signalling)

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14 pages, 1758 KiB

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AMPK: An Epigenetic Landscape Modulator

by Brendan Gongol, Indah Sari, Tiffany Bryant, Geraldine Rosete and Traci Marin

Int. J. Mol. Sci. 2018, 19(10), 3238; https://doi.org/10.3390/ijms19103238 - 19 Oct 2018

Cited by 46 | Viewed by 6809

Abstract

Activated by AMP-dependent and -independent mechanisms, AMP-activated protein kinase (AMPK) plays a central role in the regulation of cellular bioenergetics and cellular survival. AMPK regulates a diverse set of signaling networks that converge to epigenetically mediate transcriptional events. Reversible histone and DNA modifications, [...] Read more.

Activated by AMP-dependent and -independent mechanisms, AMP-activated protein kinase (AMPK) plays a central role in the regulation of cellular bioenergetics and cellular survival. AMPK regulates a diverse set of signaling networks that converge to epigenetically mediate transcriptional events. Reversible histone and DNA modifications, such as acetylation and methylation, result in structural chromatin alterations that influence transcriptional machinery access to genomic regulatory elements. The orchestration of these epigenetic events differentiates physiological from pathophysiological phenotypes. AMPK phosphorylation of histones, DNA methyltransferases and histone post-translational modifiers establish AMPK as a key player in epigenetic regulation. This review focuses on the role of AMPK as a mediator of cellular survival through its regulation of chromatin remodeling and the implications this has for health and disease. Full article

(This article belongs to the Special Issue AMP-Activated Protein Kinase Signalling)

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20 pages, 902 KiB

Open AccessReview

The Role of AMPK in the Regulation of Skeletal Muscle Size, Hypertrophy, and Regeneration

by David M. Thomson

Int. J. Mol. Sci. 2018, 19(10), 3125; https://doi.org/10.3390/ijms19103125 - 11 Oct 2018

Cited by 181 | Viewed by 22868

Abstract

AMPK (5’-adenosine monophosphate-activated protein kinase) is heavily involved in skeletal muscle metabolic control through its regulation of many downstream targets. Because of their effects on anabolic and catabolic cellular processes, AMPK plays an important role in the control of skeletal muscle development and [...] Read more.

AMPK (5’-adenosine monophosphate-activated protein kinase) is heavily involved in skeletal muscle metabolic control through its regulation of many downstream targets. Because of their effects on anabolic and catabolic cellular processes, AMPK plays an important role in the control of skeletal muscle development and growth. In this review, the effects of AMPK signaling, and those of its upstream activator, liver kinase B1 (LKB1), on skeletal muscle growth and atrophy are reviewed. The effect of AMPK activity on satellite cell-mediated muscle growth and regeneration after injury is also reviewed. Together, the current data indicate that AMPK does play an important role in regulating muscle mass and regeneration, with AMPKα1 playing a prominent role in stimulating anabolism and in regulating satellite cell dynamics during regeneration, and AMPKα2 playing a potentially more important role in regulating muscle degradation during atrophy. Full article

(This article belongs to the Special Issue AMP-Activated Protein Kinase Signalling)

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17 pages, 749 KiB

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Nutritional Modulation of AMPK-Impact upon Metabolic-Inflammation

by Claire L. Lyons and Helen M. Roche

Int. J. Mol. Sci. 2018, 19(10), 3092; https://doi.org/10.3390/ijms19103092 - 9 Oct 2018

Cited by 126 | Viewed by 18847

Abstract

Nutritional status provides metabolic substrates to activate AMP-Activated Protein Kinase (AMPK), the energy sensor that regulates metabolism. Recent evidence has demonstrated that AMPK has wider functions with respect to regulating immune cell metabolism and function. One such example is the regulatory role that [...] Read more.

Nutritional status provides metabolic substrates to activate AMP-Activated Protein Kinase (AMPK), the energy sensor that regulates metabolism. Recent evidence has demonstrated that AMPK has wider functions with respect to regulating immune cell metabolism and function. One such example is the regulatory role that AMPK has on NLRP3-inlflammasome and IL-1β biology. This in turn can result in subsequent negative downstream effects on glucose, lipid and insulin metabolism. Nutrient stress in the form of obesity can impact AMPK and whole-body metabolism, leading to complications such as type 2 diabetes and cancer risk. There is a lack of data regarding the nature and extent that nutrient status has on AMPK and metabolic-inflammation. However, emerging work elucidates to a direct role of individual nutrients on AMPK and metabolic-inflammation, as a possible means of modulating AMPK activity. The posit being to use such nutritional agents to re-configure metabolic-inflammation towards more oxidative phosphorylation and promote the resolution of inflammation. The complex paradigm will be discussed within the context of if/how dietary components, nutrients including fatty acids and non-nutrient food components, such as resveratrol, berberine, curcumin and the flavonoid genistein, modulate AMPK dependent processes relating to inflammation and metabolism. Full article

(This article belongs to the Special Issue AMP-Activated Protein Kinase Signalling)

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13 pages, 415 KiB

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AMP-Activated Protein (AMPK) in Pathophysiology of Pregnancy Complications

by Asako Kumagai, Atsuo Itakura, Daisuke Koya and Keizo Kanasaki

Int. J. Mol. Sci. 2018, 19(10), 3076; https://doi.org/10.3390/ijms19103076 - 9 Oct 2018

Cited by 30 | Viewed by 5826

Abstract

Although the global maternal mortality ratio has been consistently reduced over time, in 2015, there were still 303,000 maternal deaths throughout the world, of which 99% occurred in developing countries. Understanding pathophysiology of pregnancy complications contributes to the proper prenatal care for the [...] Read more.

Although the global maternal mortality ratio has been consistently reduced over time, in 2015, there were still 303,000 maternal deaths throughout the world, of which 99% occurred in developing countries. Understanding pathophysiology of pregnancy complications contributes to the proper prenatal care for the reduction of prenatal, perinatal and neonatal mortality and morbidity ratio. In this review, we focus on AMP-activated protein kinase (AMPK) as a regulator of pregnancy complications. AMPK is a serine/threonine kinase that is conserved within eukaryotes. It regulates the cellular and whole-body energy homeostasis under stress condition. The functions of AMPK are diverse, and the dysregulation of AMPK is known to correlate with many disorders such as cardiovascular disease, diabetes, inflammatory disease, and cancer. During pregnancy, AMPK is necessary for the proper placental differentiation, nutrient transportation, maternal and fetal energy homeostasis, and protection of the fetal membrane. Activators of AMPK such as 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR), resveratrol, and metformin restores pregnancy complications such as gestational diabetes mellitus (GDM), preeclampsia, intrauterine growth restriction, and preterm birth preclinically. We also discuss on the relationship between catechol-O-methyltransferase (COMT), an enzyme that metabolizes catechol, and AMPK during pregnancy. It is known that metformin cannot activate AMPK in COMT deficient mice, and that 2-methoxyestradiol (2-ME), a metabolite of COMT, recovers the AMPK activity, suggesting that COMT is a regulator of AMPK. These reports suggest the therapeutic use of AMPK activators for various pregnancy complications, however, careful analysis is required for the safe use of AMPK activators since AMPK activation could cause fetal malformation. Full article

(This article belongs to the Special Issue AMP-Activated Protein Kinase Signalling)

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18 pages, 1146 KiB

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Implication and Regulation of AMPK during Physiological and Pathological Myeloid Differentiation

by Arnaud Jacquel, Frederic Luciano, Guillaume Robert and Patrick Auberger

Int. J. Mol. Sci. 2018, 19(10), 2991; https://doi.org/10.3390/ijms19102991 - 30 Sep 2018

Cited by 33 | Viewed by 8973

Abstract

AMP-activated protein kinase (AMPK) is a heterotrimeric serine/threonine kinase consisting of the arrangement of various α β, and γ isoforms that are expressed differently depending on the tissue or the cell lineage. AMPK is one of the major sensors of energy status in [...] Read more.

AMP-activated protein kinase (AMPK) is a heterotrimeric serine/threonine kinase consisting of the arrangement of various α β, and γ isoforms that are expressed differently depending on the tissue or the cell lineage. AMPK is one of the major sensors of energy status in mammalian cells and as such plays essential roles in the regulation of cellular homeostasis, metabolism, cell growth, differentiation, apoptosis, and autophagy. AMPK is activated by two upstream kinases, the tumor suppressor liver kinase B1 (LKB1) and the calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) through phosphorylation of the kinase on Thr172, leading to its activation. In addition, AMPK inhibits the mTOR pathway through phosphorylation and activation of tuberous sclerosis protein 2 (TSC2) and causes direct activation of unc-51-like autophagy activating kinase 1 (ULK1) via phosphorylation of Ser555, thus promoting initiation of autophagy. Although it is well established that AMPK can control the differentiation of different cell lineages, including hematopoietic stem cells (HSCs), progenitors, and mature hematopoietic cells, the role of AMPK regarding myeloid cell differentiation is less documented. The differentiation of monocytes into macrophages triggered by colony stimulating factor 1 (CSF-1), a process during which both caspase activation (independently of apoptosis induction) and AMPK-dependent stimulation of autophagy are necessary, is one noticeable example of the involvement of AMPK in the physiological differentiation of myeloid cells. The present review focuses on the role of AMPK in the regulation of the physiological and pathological differentiation of myeloid cells. The mechanisms of autophagy induction by AMPK will also be addressed, as autophagy has been shown to be important for differentiation of hematopoietic cells. In addition, myeloid malignancies (myeloid leukemia or dysplasia) are characterized by profound defects in the establishment of proper differentiation programs. Reinduction of a normal differentiation process in myeloid malignancies has thus emerged as a valuable and promising therapeutic strategy. As AMPK seems to exert a key role in the differentiation of myeloid cells, notably through induction of autophagy, we will also discuss the potential to target this pathway as a pro-differentiating and anti-leukemic strategy in myeloid malignancies. Full article

(This article belongs to the Special Issue AMP-Activated Protein Kinase Signalling)

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8 pages, 468 KiB

Open AccessReview

Is TAK1 a Direct Upstream Kinase of AMPK?

by Dietbert Neumann

Int. J. Mol. Sci. 2018, 19(8), 2412; https://doi.org/10.3390/ijms19082412 - 15 Aug 2018

Cited by 67 | Viewed by 6596

Abstract

Alongside Liver kinase B1 (LKB1) and Ca²⁺/Calmodulin-dependent protein kinase kinase 2 (CaMKK2), Transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) has been suggested as a direct upstream kinase of AMP-activated protein kinase (AMPK). Several subsequent studies have reported on the TAK1-AMPK relationship, [...] Read more.

Alongside Liver kinase B1 (LKB1) and Ca²⁺/Calmodulin-dependent protein kinase kinase 2 (CaMKK2), Transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) has been suggested as a direct upstream kinase of AMP-activated protein kinase (AMPK). Several subsequent studies have reported on the TAK1-AMPK relationship, but the interpretation of the respective data has led to conflicting views. Therefore, to date the acceptance of TAK1 as a genuine AMPK kinase is lagging behind. This review provides with argumentation, whether or not TAK1 functions as a direct upstream kinase of AMPK. Several specific open questions that may have precluded the consensus are discussed based on available data. In brief, TAK1 can function as direct AMPK upstream kinase in specific contexts and in response to a subset of TAK1 activating stimuli. Further research is needed to define the intricate signals that are conditional for TAK1 to phosphorylate and activate AMPKα at T172. Full article

(This article belongs to the Special Issue AMP-Activated Protein Kinase Signalling)

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17 pages, 1126 KiB

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Implications of AMPK in the Formation of Epithelial Tight Junctions

by Pascal Rowart, Jingshing Wu, Michael J. Caplan and François Jouret

Int. J. Mol. Sci. 2018, 19(7), 2040; https://doi.org/10.3390/ijms19072040 - 13 Jul 2018

Cited by 54 | Viewed by 6761

Abstract

Tight junctions (TJ) play an essential role in the epithelial barrier. By definition, TJ are located at the demarcation between the apical and baso-lateral domains of the plasma membrane in epithelial cells. TJ fulfill two major roles: (i) TJ prevent the mixing of [...] Read more.

Tight junctions (TJ) play an essential role in the epithelial barrier. By definition, TJ are located at the demarcation between the apical and baso-lateral domains of the plasma membrane in epithelial cells. TJ fulfill two major roles: (i) TJ prevent the mixing of membrane components; and (ii) TJ regulate the selective paracellular permeability. Disruption of TJ is regarded as one of the earliest hallmarks of epithelial injury, leading to the loss of cell polarity and tissue disorganization. Many factors have been identified as modulators of TJ assembly/disassembly. More specifically, in addition to its role as an energy sensor, adenosine monophosphate-activated protein kinase (AMPK) participates in TJ regulation. AMPK is a ubiquitous serine/threonine kinase composed of a catalytic α-subunit complexed with regulatory β-and γ-subunits. AMPK activation promotes the early stages of epithelial TJ assembly. AMPK phosphorylates the adherens junction protein afadin and regulates its interaction with the TJ-associated protein zonula occludens (ZO)-1, thereby facilitating ZO-1 distribution to the plasma membrane. In the present review, we detail the signaling pathways up-and down-stream of AMPK activation at the time of Ca²⁺-induced TJ assembly. Full article

(This article belongs to the Special Issue AMP-Activated Protein Kinase Signalling)

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13 pages, 845 KiB

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AMP-Activated Protein Kinase as a Reprogramming Strategy for Hypertension and Kidney Disease of Developmental Origin

by You-Lin Tain and Chien-Ning Hsu

Int. J. Mol. Sci. 2018, 19(6), 1744; https://doi.org/10.3390/ijms19061744 - 12 Jun 2018

Cited by 60 | Viewed by 4987

Abstract

Suboptimal early-life conditions affect the developing kidney, resulting in long-term programming effects, namely renal programming. Adverse renal programming increases the risk for developing hypertension and kidney disease in adulthood. Conversely, reprogramming is a strategy aimed at reversing the programming processes in early life. [...] Read more.

Suboptimal early-life conditions affect the developing kidney, resulting in long-term programming effects, namely renal programming. Adverse renal programming increases the risk for developing hypertension and kidney disease in adulthood. Conversely, reprogramming is a strategy aimed at reversing the programming processes in early life. AMP-activated protein kinase (AMPK) plays a key role in normal renal physiology and the pathogenesis of hypertension and kidney disease. This review discusses the regulation of AMPK in the kidney and provides hypothetical mechanisms linking AMPK to renal programming. This will be followed by studies targeting AMPK activators like metformin, resveratrol, thiazolidinediones, and polyphenols as reprogramming strategies to prevent hypertension and kidney disease. Further studies that broaden our understanding of AMPK isoform- and tissue-specific effects on renal programming are needed to ultimately develop reprogramming strategies. Despite the fact that animal models have provided interesting results with regard to reprogramming strategies targeting AMPK signaling to protect against hypertension and kidney disease with developmental origins, these results await further clinical translation. Full article

(This article belongs to the Special Issue AMP-Activated Protein Kinase Signalling)

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