Insulin attenuates apoptosis induced by high glucose via the PI3-kinase/Akt pathway in rat peritoneal mesothelial cells

Kaifu, Kumiko; Kiyomoto, Hideyasu; Hitomi, Hirofumi; Matsubara, Keisuke; Hara, Taiga; Moriwaki, Kumiko; Ihara, Genei; Fujita, Yoshiko; Sugasawa, Noriko; Nagata, Daisuke; Nishiyama, Akira; Kohno, Masakazu

doi:10.1093/ndt/gfn598

Cited by 18 publications

(15 citation statements)

References 37 publications

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“…Furthermore, the development of a novel delivery system to increase local concentrations in the lung epithelial cell milieu without hypoglycemia is a prerequisite for clinical application of insulin to lung diseases, because it was shown that circulating insulin levels with intensive insulin therapy are only transiently higher than in conventional treatment (5), and the antiapoptotic effect of insulin occurred in our in vitro model at concentrations 10-fold higher than physiological levels during a nonfasting state. However, it is not unexpected that more than physiological levels of insulin might be indispensable to demonstrate the antiapoptotic effect, especially in in vitro experimental conditions as used in recent studies (27,41).…”

Section: Discussionmentioning

confidence: 99%

Insulin-Dependent Phosphatidylinositol 3-Kinase/Akt and ERK Signaling Pathways Inhibit TLR3-Mediated Human Bronchial Epithelial Cell Apoptosis

Numata

Araya

Fujii

et al. 2011

The Journal of Immunology

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TLR3, one of the TLRs involved in the recognition of infectious pathogens for innate and adaptive immunity, primarily recognizes viral-associated dsRNA. Recognition of dsRNA byproducts released from apoptotic and necrotic cells is a recently proposed mechanism for the amplification of toxicity, suggesting a pivotal participation of TLR3 in viral infection, as well as in lung diseases where apoptosis plays a critical role, such as asthma and chronic obstructive pulmonary disease. In addition to metabolic control, insulin signaling was postulated to be protective by inhibiting apoptosis. Therefore, we explored the role of insulin signaling in protecting against TLR3-mediated apoptosis of human bronchial epithelial cells. Significant TLR3-mediated apoptosis was induced by polyinosinic-polycytidylic acid, a dsRNA analog, via caspase-8–dependent mechanisms. However, insulin efficiently inhibited TLR3/ polyinosinic-polycytidylic acid-induced human bronchial epithelial cell apoptosis via PI3K/Akt and ERK pathways, at least in part, via upregulation of cellular FLIPs and through protein synthesis-independent mechanisms. These results indicate the significance of TLR3-mediated dsRNA-induced apoptosis in the pathogenesis of apoptosis-driven lung disease and provide evidence for a novel protective role of insulin.

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Section: Discussionmentioning

confidence: 99%

Insulin-Dependent Phosphatidylinositol 3-Kinase/Akt and ERK Signaling Pathways Inhibit TLR3-Mediated Human Bronchial Epithelial Cell Apoptosis

Numata

Araya

Fujii

et al. 2011

The Journal of Immunology

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“…Carbon monoxide (CO) (210) can be one of the activators of this pathway in the lung, but insulin can also activate this pathway, which has been demonstrated in other tissues (95,176). PI3K/Akt activates p38 mitogen-activated protein kinase, which activates STAT3, a member of a transcription factor family that decreases Fas expression and caspase-3 activation (210).…”

Section: H1288 Molecular Mechanisms Of Lung Ischemia-reperfusion Injurymentioning

confidence: 99%

Lung ischemia-reperfusion injury: a molecular and clinical view on a complex pathophysiological process

Hengst

Gielis

Lin

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

316

280

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Lung ischemia-reperfusion injury remains one of the major complications after cardiac bypass surgery and lung transplantation. Due to its dual blood supply system and the availability of oxygen from alveolar ventilation, the pathogenetic mechanisms of ischemia-reperfusion injury in the lungs are more complicated than in other organs, where loss of blood flow automatically leads to hypoxia. In this review, an extensive overview is given of the molecular and cellular mechanisms that are involved in the pathogenesis of lung ischemia-reperfusion injury and the possible therapeutic strategies to reduce or prevent it. In addition, the roles of neutrophils, alveolar macrophages, cytokines, and chemokines, as well as the alterations in the cell-death related pathways, are described in detail. pulmonary; lung transplantation; ventilated ischemia IN THE PAST, THE LUNG WAS thought to be relatively resistant to ischemia because of its dual circulation and the availability of oxygen from alveolar ventilation. However, the depletion of lung oxygenation by stopping the ventilation leads to the same degree of lung impairment as a decrease in mechanotransduction by loss of blood flow, as determined by increases in vascular pressure and permeability (11), indicating that any deficiency from oxygenation or mechanotransduction can have significant repercussions (149).Reperfusion of the ischemic lung is a double-edged sword. Reestablishing the perfusion of the ischemic lung is absolutely required to maintain the viability of the lung, but reperfusion itself can trigger a complex cascade of events, the so-called pulmonary ischemia-reperfusion injury (LIRI) (48), characterized by increased microvascular permeability (Pvasc), increased pulmonary vascular resistance (PVR), pulmonary edema, impaired oxygenation, and pulmonary hypertension. Ischemia of the lung, without loss of ventilation, results in a complex pathophysiological situation and, therefore, is not comparable with ischemia in other organs. During ventilated ischemia, for example, the adenosine triphosphate (ATP) levels remain normal while reactive oxygen species (ROS) are formed (70), illustrating aspects of complexity of the pathophysiology of ventilated and anoxic lung ischemia. Therefore, a distinction should be made between ventilated ischemia, meaning a loss of blood flow, and anoxia/reoxygenation, indicating the loss of oxygenation and/or perfusion. In this review, the terms anoxia/reoxygenation and ventilated ischemia will be used, if the specific model is known and/or the mechanism is suggested to be model specific. Ischemia alone will be used, if it applies for both mechanisms, if the specific model is not known, or the research involves other organs.Complete and prolonged lung anoxia for up to several hours is unavoidable during lung transplantation, with dire consequences. Reperfusion of the transplanted lung can lead to nonspecific alveolar damage, pulmonary edema, and hypoxemia within 72 h after lung transplantation. Even with the advancements in lung preservati...

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“…These pathways phosphorylate serine residues in several subunits of NAD(P)H oxidase (el Benna et al, 1994; Park and Babior, 1997; Dang et al, 1999; Lopes et al, 1999; Babior, 2002, 2004; Simon and Stutzin, 2008). Additionally, it has been reported in rat peritoneal mesothelial cell (RPMC) the participation of the PI3K/Akt pathway in RPMC death induced by high glucose (Kaifu et al, 2009), suggesting that a similar mechanism was implicated in human cells. However, it is unknown if these signaling pathways are involved in HGH solution-induced human peritoneal mesothelial cell (HPMC) death.…”

Section: Introductionmentioning

confidence: 99%

Human Peritoneal Mesothelial Cell Death Induced by High-Glucose Hypertonic Solution Involves Ca2+ and Na+ Ions and Oxidative Stress with the Participation of PKC/NOX2 and PI3K/Akt Pathways

Simón

Tapía²,

Armisén

et al. 2017

Front. Physiol.

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Chronic peritoneal dialysis (PD) therapy is equally efficient as hemodialysis while providing greater patient comfort and mobility. Therefore, PD is the treatment of choice for several types of renal patients. During PD, a high-glucose hyperosmotic (HGH) solution is administered into the peritoneal cavity to generate an osmotic gradient that promotes water and solutes transport from peritoneal blood to the dialysis solution. Unfortunately, PD has been associated with a loss of peritoneal viability and function through the generation of a severe inflammatory state that induces human peritoneal mesothelial cell (HPMC) death. Despite this deleterious effect, the precise molecular mechanism of HPMC death as induced by HGH solutions is far from being understood. Therefore, the aim of this study was to explore the pathways involved in HGH solution-induced HPMC death. HGH-induced HPMC death included influxes of intracellular Ca2+ and Na+. Furthermore, HGH-induced HPMC death was inhibited by antioxidant and reducing agents. In line with this, HPMC death was induced solely by increased oxidative stress. In addition to this, the cPKC/NOX2 and PI3K/Akt intracellular signaling pathways also participated in HGH-induced HPMC death. The participation of PI3K/Akt intracellular is in agreement with previously shown in rat PMC apoptosis. These findings contribute toward fully elucidating the underlying molecular mechanism mediating peritoneal mesothelial cell death induced by high-glucose solutions during peritoneal dialysis.

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Insulin attenuates apoptosis induced by high glucose via the PI3-kinase/Akt pathway in rat peritoneal mesothelial cells

Cited by 18 publications

References 37 publications

Insulin-Dependent Phosphatidylinositol 3-Kinase/Akt and ERK Signaling Pathways Inhibit TLR3-Mediated Human Bronchial Epithelial Cell Apoptosis

Insulin-Dependent Phosphatidylinositol 3-Kinase/Akt and ERK Signaling Pathways Inhibit TLR3-Mediated Human Bronchial Epithelial Cell Apoptosis

Lung ischemia-reperfusion injury: a molecular and clinical view on a complex pathophysiological process

Human Peritoneal Mesothelial Cell Death Induced by High-Glucose Hypertonic Solution Involves Ca2+ and Na+ Ions and Oxidative Stress with the Participation of PKC/NOX2 and PI3K/Akt Pathways

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