Intermittent But Not Constant High Glucose Induces ER Stress and Inflammation in Human Retinal Pericytes

Zhong, Yimin; Wang, Joshua J.; Zhang, Sarah X.

doi:10.1007/978-1-4614-0631-0_37

Cited by 45 publications

(40 citation statements)

References 11 publications

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“…Induction of ER stress in the retina by intravitreal injection of tunicamycin was sufficient to induce retinal VEGF expression in mice. In parallel, exposure of retinal vascular endothelial cells or Müller cells to tunicamycin or thapsigargin also induced a significant increase in VEGF expression (Li et al, 2009; Zhong et al, 2012a)(Chen, Wang et al 2012). Conversely, reduction of ER stress attenuated VEGF production in cultured retinal cells and in the diabetic retina, as well as in the ischemic retina from mice with oxygen-induced retinopathy (OIR) (Li et al, 2009).…”

Section: Er Stress and Neovascular Retinal Diseasesmentioning

confidence: 89%

The unfolded protein response in retinal vascular diseases: Implications and therapeutic potential beyond protein folding

Zhang

Jacey

Bhatta

et al. 2015

Progress in Retinal and Eye Research

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Angiogenesis is a complex, step-wise process of new vessel formation that is involved in both normal embryonic development as well as postnatal pathological processes, such as cancer, cardiovascular disease, and diabetes. Aberrant blood vessel growth, also known as neovascularization, in the retina and the choroid is a major cause of vision loss in severe eye diseases, such as diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity, and central and branch retinal vein occlusion. Yet, retinal neovascularization is causally and dynamically associated with vasodegeneration, ischemia, and vascular remodeling in retinal tissues. Understanding the mechanisms of retinal neovascularization is an urgent unmet need for developing new treatments for these devastating diseases. Accumulating evidence suggests a vital role for the unfolded protein response (UPR) in regulation of angiogenesis, in part through coordinating the secretion of pro-angiogenic growth factors, such as VEGF, and modulating endothelial cell survival and activity. Herein, we summarize current research in the context of endoplasmic reticulum (ER) stress and UPR signaling in retinal angiogenesis and vascular remodeling, highlighting potential implications of targeting these stress response pathways in the prevention and treatment of retinal vascular diseases that result in visual deficits and blindness.

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Section: Er Stress and Neovascular Retinal Diseasesmentioning

confidence: 89%

The unfolded protein response in retinal vascular diseases: Implications and therapeutic potential beyond protein folding

Zhang

Jacey

Bhatta

et al. 2015

Progress in Retinal and Eye Research

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“…Stimuli that increase the demand on the ER to synthesize proteins or degrade improperly folded proteins cause this stress. Several components of the diabetic milieu, i.e., high glucose, free fatty acids, albumin, oxidative activity and inflammation, induce ER stress in numerous tissues (12)(13)(14). However, prolonged activation of ER stress ultimately initiates the apoptotic pathway.…”

Section: Introductionmentioning

confidence: 99%

C/EBP homologous protein induces mesangial cell apoptosis under hyperglycemia

Zhao

et al. 2012

Molecular Medicine Reports

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Abstract. Diabetes mellitus is known to cause kidney impairment; however, the mechanism remains elusive. The aim of this study was to investigate the role of C/EBP homologous protein (CHOP), an important protein in endoplasmic reticulum stress-mediated mesangial cell apoptosis in hyperglycemia. Mesangial cells were cultured in normal (control group) and high glucose medium (high glucose group). TUNEL staining was performed to assess apoptotic cells in the groups. The expression of CHOP and caspase-3 was also assayed by immunohistochemistry and western blot analysis. Following 24 h culture in high glucose medium, TUNEL-positive cells were observed to be significantly increased (P<0.01). The expression of CHOP and caspase-3 in mesangial cells was also found to be significantly enhanced under high glucose conditions compared with the normal group (P<0.01). The results indicate that CHOP mediates apoptosis in mesangial cells under hyperglycemia and may play a role in the development of diabetic nephropathy.

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“…In Type 1 DM patients with diabetic ketoacidosis (DKA), brain edema is a frequent occurrence and results from neuroinflammation and TJ compromise (Zhong et al, 2012). DKA is associated with high levels of serum IL-6, and an abundance of CCL2, NF-κB, and nitrotyrosine found in brain tissue by neuropathologic examination (Yorulmaz et al, 2015).…”

Section: Endothelial Cell Dysfunctionmentioning

confidence: 99%

“…This effect was RAGE-dependent, accompanied by increased permeability, and required the same autocrine action of VEGF as seen HG. Changes in TJ after exposure to AGEs is mediated by matrix MMPs (Hawkins et al, 2007; Zhong et al, 2012; Shimizu et al, 2013; Persidsky et al, 2016) A drop in occludin and ZO-1 expression was associated with increasing MMPs in rat and human DM (Zhong et al, 2012; Shah et al, 2013), and inhibition of MMP-9 prevented increased permeability in streptozotocin (STZ)-induced DM in mice(Shimizu et al, 2013). The AGEs-mediated decrease in claudin-5 in vitro can be abolished through blockade of MMPs(Wang et al, 2012a), further suggesting that MMPs are necessary for AGEs-mediated damage (Figure 2).…”

Section: Endothelial Cell Dysfunctionmentioning

confidence: 99%

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Blood Brain Barrier Injury in Diabetes: Unrecognized Effects on Brain and Cognition

Bogush

Heldt

Persidsky

2017

J Neuroimmune Pharmacol

121

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Diabetes mellitus (DM) is a disorder due to the inability properly to metabolize glucose associated with dysregulation of metabolic pathways of lipids and proteins resulting in structural and functional changes of various organ systems. DM has detrimental effects on the vasculature, resulting in the development of various cardiovascular diseases and stemming from microvascular injury. The blood brain barrier (BBB) is a highly specialized structure protecting the unique microenvironment of the brain. Endothelial cells, connected by junctional complexes and expressing numerous transporters, constitute the main cell type in the BBB. Other components, including pericytes, basement membrane, astrocytes and perivascular macrophages, join endothelial cells to form the neurovascular unit (NVU) and contribute to the proper function and integrity of the BBB. The role of the BBB in the pathogenesis of diabetic encephalopathy and other diabetes-related complications in the central nervous system is apparent. However, the mechanisms, timing and consequences of BBB injury in diabetes are not well understood. The importance of further studies related to barrier dysfunction in diabetes is dictated by its potential involvement in the cognitive demise associated with DM. This review summarizes the impact of DM on BBB/NVU integrity and function leading to neurological and cognitive complications.

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Intermittent But Not Constant High Glucose Induces ER Stress and Inflammation in Human Retinal Pericytes

Cited by 45 publications

References 11 publications

The unfolded protein response in retinal vascular diseases: Implications and therapeutic potential beyond protein folding

The unfolded protein response in retinal vascular diseases: Implications and therapeutic potential beyond protein folding

C/EBP homologous protein induces mesangial cell apoptosis under hyperglycemia

Blood Brain Barrier Injury in Diabetes: Unrecognized Effects on Brain and Cognition

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