Role of the PKCβII/JNK signaling pathway in acute glucose fluctuation-induced apoptosis of rat vascular endothelial cells

Wu, Na; Shen, Haitao; Wang, Yanjun; He, Bing; Zhang, Yongyan; Bai, Yu; Du, Runyu; Du, Qiang; Han, Ping

doi:10.1007/s00592-017-0999-5

Cited by 8 publications

(10 citation statements)

References 27 publications

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“…Glucose fluctuations can promote overproduction of adhesion molecules by activating PKC-β, completely dependent from mitochondrial superoxide over-production in human umbilical vein endothelial cells (98). Na et al (99) suggested that PKC-βII membrane translocation increased in endothelial cells with acute glucose fluctuations (100). The activation of JNK can be mediated by PKC-βII and plays an important role in apoptosis of endothelial cells (101).…”

Section: Possible Mechanisms Mediated By Glucose Fluctuationsmentioning

confidence: 99%

Molecular Mechanisms of Glucose Fluctuations on Diabetic Complications

et al. 2019

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Accumulating evidence indicates the occurrence and development of diabetic complications relates to not only constant high plasma glucose, but also glucose fluctuations which affect various kinds of molecular mechanisms in various target cells and tissues. In this review, we detail reactive oxygen species and their potentially damaging effects upon glucose fluctuations and resultant downstream regulation of protein signaling pathways, including protein kinase C, protein kinase B, nuclear factor-κB, and the mitogen-activated protein kinase signaling pathway. A deeper understanding of glucose-fluctuation-related molecular mechanisms in the development of diabetic complications may enable more potential target therapies in future.

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Section: Possible Mechanisms Mediated By Glucose Fluctuationsmentioning

confidence: 99%

Molecular Mechanisms of Glucose Fluctuations on Diabetic Complications

et al. 2019

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“…The in vitro model of the iBRB we re-created using species-specific cells only is meant as close as possible to the human retinal microenvironment in diabetic-like conditions: pericytes and Müller cells are of retinal origin, while HMECs, though derma-derived, are largely used as models for the study of various diseases, including DR [19]. We chose intermittent high glucose conditions for our experimental setting, because HRP, ECs and Müller cells are more sensitive to intermittent than stable high glucose [16,20,21] and, in real life, diabetic patients are continuously subjected to glucose fluctuations. It has also been postulated that glycemic excursions may cause retinal neurodegeneration in type 1 diabetes [22].…”

Section: Discussionmentioning

confidence: 99%

Effects of thiamine and fenofibrate on high glucose and hypoxia-induced damage in cell models of the inner blood-retinal barrier

et al. 2020

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Aims: Although diabetic retinopathy has long been considered a microvascular complication, retinal neurodegeneration and inflammation may precede its clinical manifestations. Despite all research efforts, the primary treatment options remain laser photocoagulation and anti-vascular endothelial growth factor (VEGF) intravitreal injections, both aggressive and targeting the late stages of the disease. Medical treatments addressing the early phases of diabetic retinopathy are therefore needed. We aimed at verifying if thiamine and fenofibrate protect the cells of the inner blood-retinal barrier from the metabolic stress induced by diabetic-like conditions. Methods: Human microvascular endothelial cells (HMECs), retinal pericytes (HRPs) and Müller cells (MIO-M1) were cultured in intermittent high glucose (intHG) and/or hypoxia, with addition of fenofibrate or thiamine. Modulation of adhesion molecules and angiogenic factors was addressed. Results: Integrins β1/αVβ3 and ICAM1 were upregulated in HMECs/HRPs cultured in diabetic-like conditions, as well as metalloproteases MMP2/9 in HRP, with a reduction of their inhibitor TIMP1; MMP2 increased also in HMEC, and TIMP1 decreased in MIO-M1. VEGF and HIF-1α were strongly increased in HMEC in intHG+hypoxia, and VEGF also in HRP. Ang-1/2 augmented in HMEC/MIO-M1, and MCP-1 in HRP/MIO-M1 in intHG+hypoxia. Thiamine was able to normalize all such abnormal modulations, while fenofibrate had effects in few cases only. Conclusions: We suggest that endothelial cells and pericytes are more affected than Müller cells by diabetic-like conditions. Fenofibrate shows a controversial behavior, potentially positive on Müller cells and pericytes, but possibly detrimental to endothelium, while thiamine confirms once more to be an effective agent in reducing diabetes-induced retinal damage.

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“…The membrane translocation or activation of PKC isoforms is linked to the development of pathologies in diabetes. The acute blood glucose fluctuation significantly increased cPKC β II membrane translocation, which causes the apoptosis of vascular endothelial cell through increasing oxidative stress and induces impairment of insulin signaling in diabetic rats [ 11 ]. Activation of cPKC β II by hyperglycemia upregulates caspase 8-induced apoptosis in blood-brain barrier endothelial cells [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

“…Deletion or inhibition of the cPKC β II can reduce glomerular, albuminuria, and mesangial expansion, which prevent the thickening of the glomerular basement membrane and the obliteration of glomerular capillaries in a diabetic kidney [ 15 , 16 ]. The cPKC β II inhibitor can reverse acute blood glucose fluctuation-induced endothelial cell apoptosis increase, inflammatory cytokine level increase, and insulin signaling impairment, indicating that PKC β II may serve as a target for anticardiovascular diseases [ 11 ]. The cPKC β II inhibitor can also reduce the incidence of visual loss and prevent blood-retinal barrier breakdown in diabetic patients and animal models [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Identification of Protein Kinase C Isoforms Involved in Type 1 Diabetic Encephalopathy in Mice

Zheng

Wang

Han

et al. 2018

Journal of Diabetes Research

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Diabetic encephalopathy is a complication of diabetes mellitus characterized by impaired cognitive functions. Protein kinase C (PKC) isoforms are rarely reported on diabetic encephalopathy, although they have been believed to play crucial roles in other diabetic complications. In this study, streptozotocin- (STZ-) induced diabetic mice were found to exhibit learning and memory deficits in the Morris water maze test. Meanwhile, the expression of cPKCβII, nPKCε, and cPKCγ did not change in the hippocampus, cortex, and striatum at 2 and 8 weeks after STZ injection. The nPKCε translocation to the membrane, where it is activated, was not altered in the above brain regions at 2 and 8 weeks after STZ injection. Nevertheless, cPKCβII translocation to the membrane was significantly decreased in the cortex and hippocampus at 8 weeks after STZ injection. The translocation of cPKCγ from the cytosol to the membrane was remarkably decreased in the hippocampus at 2 and 8 weeks and in the cortex and striatum at 8 weeks after STZ injection. In addition, deletion of cPKCγ aggravated the impairment of spatial learning and memory. In conclusion, our results suggest that the decrease in the activity of cPKCβII and cPKCγ, especially cPKCγ, may play key roles in the pathogenesis of diabetic encephalopathy.

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Role of the PKCβII/JNK signaling pathway in acute glucose fluctuation-induced apoptosis of rat vascular endothelial cells

Abstract: It is necessary to actively control blood glucose and avoid significant glucose fluctuation. PKCβII/JNK may serve as a target, and inhibitors of PKCβII/JNK may be used to help prevent cardiovascular diseases in patients with poor glucose control or significant glucose fluctuation.

Cited by 8 publications

References 27 publications

Molecular Mechanisms of Glucose Fluctuations on Diabetic Complications

Molecular Mechanisms of Glucose Fluctuations on Diabetic Complications

Effects of thiamine and fenofibrate on high glucose and hypoxia-induced damage in cell models of the inner blood-retinal barrier

Identification of Protein Kinase C Isoforms Involved in Type 1 Diabetic Encephalopathy in Mice

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