AMP-Activated Protein Kinase Inhibits Homocysteine-Induced Dysfunction and Apoptosis in Endothelial Progenitor Cells

Jia, Fei; Wu, Chunfang; Chen, Zhenyue; Li, Guoping

doi:10.1007/s10557-010-6277-1

Cited by 19 publications

(11 citation statements)

References 31 publications

(40 reference statements)

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“…We found that AMPK activation negatively regulates the Nox4 protein expression and ROS production stimulated by HG. These observations are supported by numerous published studies showing that AMPK constitutes a physiological suppressor of ROS production via inhibition of NADPH oxidase activation and the expression of Nox subunits, including Nox4 (9,32,33,(65)(66)(67).…”

Section: Discussionsupporting

confidence: 64%

Sestrin 2 and AMPK Connect Hyperglycemia to Nox4-Dependent Endothelial Nitric Oxide Synthase Uncoupling and Matrix Protein Expression

Eid

Lee

Roman

et al. 2013

Molecular and Cellular Biology

119

121

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Mesangial matrix accumulation is an early feature of glomerular pathology in diabetes. Oxidative stress plays a critical role in hyperglycemia-induced glomerular injury. Here, we demonstrate that, in glomerular mesangial cells (MCs), endothelial nitric oxide synthase (eNOS) is uncoupled upon exposure to high glucose (HG), with enhanced generation of reactive oxygen species (ROS) and decreased production of nitric oxide. Peroxynitrite mediates the effects of HG on eNOS dysfunction. HG upregulates Nox4 protein, and inhibition of Nox4 abrogates the increase in ROS and peroxynitrite generation, as well as the eNOS uncoupling triggered by HG, demonstrating that Nox4 functions upstream from eNOS. Importantly, this pathway contributes to HGinduced MC fibronectin accumulation. Nox4-mediated eNOS dysfunction was confirmed in glomeruli of a rat model of type 1 diabetes. Sestrin 2-dependent AMP-activated protein kinase (AMPK) activation attenuates HG-induced MC fibronectin synthesis through blockade of Nox4-dependent ROS and peroxynitrite generation, with subsequent eNOS uncoupling. We also find that HG negatively regulates sestrin 2 and AMPK, thereby promoting Nox4-mediated eNOS dysfunction and increased fibronectin. These data identify a protective function for sestrin 2/AMPK and potential targets for intervention to prevent fibrotic injury in diabetes.T he pathological manifestations of early diabetes in the glomerular microvascular bed include glomerular mesangial cell hypertrophy associated with an increase in mesangial matrix accumulation (1, 2). These events precede the development of irreversible glomerulosclerosis (1, 2). Data from animal models of diabetes, as well as from cultured cells, indicate that hyperglycemia and high glucose (HG) increase extracellular matrix expansion in mesangial cells (MCs) (1, 2).Oxidative stress with increased generation of reactive oxygen species (ROS) has emerged as a critical pathogenic factor in the development of diabetic nephropathy (DN) (1-3). However, the protective effects of traditional antioxidants are very limited. Identifying sources of ROS should help in designing rational therapy to modulate oxidative stress. Although multiple pathways may result in ROS generation, numerous studies identified NADPH oxidases of the Nox family as major sources of ROS in various nonphagocytic/stromal cells, including most kidney cells (4-6). Evidence from studies in cultured cells suggests that the isoform Nox4 is required for the damaging effects of HG that contribute to microvascular complications of diabetes in the retina, the heart, or the kidney (7-13). We have previously reported that Nox4-dependent ROS generation mediates glomerular hypertrophy and mesangial matrix accumulation in early type 1 diabetes (13). In MCs, we showed that Nox4-derived ROS result in the increased fibronectin expression induced by HG (13,14). Nevertheless, the mechanisms that Nox4 utilizes to exert this biological effect remain unclear, and the upstream regulators or downstream effectors of the oxidase are n...

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Section: Discussionsupporting

confidence: 64%

Sestrin 2 and AMPK Connect Hyperglycemia to Nox4-Dependent Endothelial Nitric Oxide Synthase Uncoupling and Matrix Protein Expression

Eid

Lee

Roman

et al. 2013

Molecular and Cellular Biology

119

121

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“…Rosiglitazone was reported to reduce glucose-induced oxidative stress (35) and stimulate nitric oxide synthesis (36) in endothelial cells via AMP-activated protein kinase (AMPK). AMPK inhibited homocysteine-induced apoptosis in EPCs and reduced reactive oxygen species (ROS) accumulation and endothelial nitric oxide synthase (eNOS) down-regulation (37). Therefore, we hypothesize that rosiglitazone may also attenuate TNF-α-induced EPC apoptosis via AMPK by reducing oxidative stress.…”

Section: Discussionmentioning

confidence: 93%

Rosiglitazone Attenuates Endothelial Progenitor Cell Apoptosis Induced by TNF-α via ERK/MAPK and NF-κB Signal Pathways

Zhao

et al. 2011

J Pharmacol Sci

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Abstract. The discovery of endothelial progenitor cells (EPCs) provides us with a novel treatment strategy for complications requiring therapeutic revascularization and vascular repair. However, the feasibility of this strategy may be limited due to reduced number and impaired function of EPCs under stimulation of TNF-α. The present study was designed to investigate the effect of rosiglitazone on EPC apoptosis induced by TNF-α and the molecular mechanisms involved. Rosiglitazone attenuated apoptosis of TNF-α-stimulated EPCs in a dose-dependent manner. Rosiglitazone decreased caspase-3 activity and cleavages of caspase-3, caspase-7, and parp. Rosiglitazone also moderated the dissipation of mitochondrial membrane potential caused by TNF-α treatment and reduced the expression of bax and the release of cytochrome c. Furthermore, rosiglitazone inhibited phosphorylations of ERK/MAPK and NF-κB signal molecules. Both ERK and NF-κB inhibitors decreased TNF-α-induced apoptosis of EPCs, as well as the expression of cleaved caspase-3 and parp. These results suggest that rosiglitazone may mediate the inhibitory effect on EPCs apoptosis under TNF-α stimulation through suppression of ERK/MAPK and NF-κB signal pathways.

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“…Metformin is known to reduce both intracellular ROS levels and NADPH oxidase 4 expression (16). Furthermore, it has been reported that AMPK can stimulate the expression of HO-1 in macrophages and endothelial cells via the induction of nuclear factor-erythroid 2-related factor 2 (28).…”

Section: Discussionmentioning

confidence: 99%

Activation of AMP-activated protein kinase inhibits ER stress and renal fibrosis

Kim

Moon

Kim

et al. 2015

American Journal of Physiology-Renal Physiology

122

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It has been suggested that endoplasmic reticulum (ER) stress facilitates fibrotic remodeling. Therefore, modulation of ER stress may serve as one of the possible therapeutic approaches to renal fibrosis. We examined whether and how activation of AMP-activated protein kinase (AMPK) suppressed ER stress induced by chemical ER stress inducers [tunicamycin (TM) and thapsigargin (TG)] and also nonchemical inducers in tubular HK-2 cells. We further investigated the in vivo effects of AMPK on ER stress and renal fibrosis. Western blot analysis, immunofluorescence, small interfering (si)RNA experiments, and immunohistochemical staining were performed. Metformin (the best known clinical activator of AMPK) suppressed TM- or TG-induced ER stress, as shown by the inhibition of TM- or TG-induced upregulation of glucose-related protein (GRP)78 and phosphorylated eukaryotic initiation factor-2α through induction of heme oxygenase-1. Metformin inhibited TM- or TG-induced epithelial-mesenchymal transitions as well. Compound C (AMPK inhibitor) blocked the effect of metformin, and 5-aminoimidazole-4-carboxamide-1β riboside (another AMPK activator) exerted the same effects as metformin. Transfection with siRNA targeting AMPK blocked the effect of metformin. Consistent with the results of cell culture experiments, metformin reduced renal cortical GRP78 expression and increased heme oxygenase-1 expression in a mouse model of ER stress-induced acute kidney injury by TM. Activation of AMPK also suppressed ER stress by transforming growth factor-β, ANG II, aldosterone, and high glucose. Furthermore, metformin reduced GRP78 expression and renal fibrosis in a mouse model of unilateral ureteral obstruction. In conclusion, AMPK may serve as a promising therapeutic target through reducing ER stress and renal fibrosis.

show abstract

AMP-Activated Protein Kinase Inhibits Homocysteine-Induced Dysfunction and Apoptosis in Endothelial Progenitor Cells

Abstract: AMPK activation inhibits eNOS down-regulation and Nox4-derived ROS accumulation induced by Hcy in EPCs, and may contribute to the protective effects of atorvastatin on endothelial function.

Cited by 19 publications

References 31 publications

Sestrin 2 and AMPK Connect Hyperglycemia to Nox4-Dependent Endothelial Nitric Oxide Synthase Uncoupling and Matrix Protein Expression

Sestrin 2 and AMPK Connect Hyperglycemia to Nox4-Dependent Endothelial Nitric Oxide Synthase Uncoupling and Matrix Protein Expression

Rosiglitazone Attenuates Endothelial Progenitor Cell Apoptosis Induced by TNF-α via ERK/MAPK and NF-κB Signal Pathways

Activation of AMP-activated protein kinase inhibits ER stress and renal fibrosis

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