TRB3 is stimulated in diabetic kidneys, regulated by the ER stress marker CHOP, and is a suppressor of podocyte MCP-1

Morse, Elizabeth M.; Schroth, Jana; You, Young Hyun; Pizzo, Donald; Okada, Shinichi; RamachandraRao, Satish P.; Vallon, Volker; Sharma, Kumar; Cunard, Robyn

doi:10.1152/ajprenal.00236.2010

Cited by 74 publications

(82 citation statements)

References 61 publications

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“…For example, ER stress-induced apoptosis requires not only CHOP (28) but also the endoribonuclease activity of IRE1␣, an independent component of the UPR (11). In contrast to its function in the setting of ER stress, CHOP can function in proinflammatory responses through direct regulation of IL-8/CXCL8 and caspase-4, a component of the inflammasome (2,3,9,38), and through indirect regulation of monocyte chemoattractant protein 1 (MCP-1/ CCL2) (24). Additionally, PKR phosphorylation is required for maximal cytokine response to Toll-like receptor (TLR)2/4 activation in macrophages (6), raising the following question: Does CHOP play an unrecognized proinflammatory role during microbial infection via a PKR-dependent mechanism?…”

Section: Discussionmentioning

confidence: 99%

PKR-dependent CHOP induction limits hyperoxia-induced lung injury

Lozon¹,

Eastman²,

Matute-Bello

et al. 2011

American Journal of Physiology-Lung Cellular and Molecular Phys

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Lozon TI, Eastman AJ, Matute-Bello G, Chen P, Hallstrand TS, Altemeier WA. PKR-dependent CHOP induction limits hyperoxia-induced lung injury. Am J Physiol Lung Cell Mol Physiol 300: L422-L429, 2011. First published December 24, 2010 doi:10.1152 doi:10. /ajplung.00166.2010 is commonly employed in patients with respiratory failure; however, hyperoxia is also a potential contributor to lung injury. In animal models, hyperoxia causes oxidative stress in the lungs, resulting in increased inflammation, edema, and permeability. We hypothesized that oxidative stress from prolonged hyperoxia leads to endoplasmic reticulum (ER) stress, resulting in activation of the unfolded protein response (UPR) and induction of CCAAT enhancer-binding protein homologous protein (CHOP), a transcription factor associated with cell death in the setting of persistent ER stress. To test this hypothesis, we exposed the mouse lung epithelial cell line MLE-12 to 95% O2 for 8 -24 h and evaluated for evidence of UPR induction and CHOP induction. Hyperoxia caused increased CHOP expression without other evidence of UPR activation. Because CHOP expression is preceded by phosphorylation of the ␣-subunit of the eukaryotic initiation factor-2 (eIF2␣), we evaluated the role of double-stranded RNA-activated protein kinase (PKR), a non-UPR-associated eIF2␣ kinase. Hyperoxia caused PKR phosphorylation, and RNA interference knockdown of PKR attenuated hyperoxia-induced CHOP expression. In vivo, hyperoxia induced PKR phosphorylation and CHOP expression in the lungs without other biochemical evidence for ER stress. Additionally, Ddit3 Ϫ/Ϫ (CHOP-null) mice had increased lung edema and permeability, indicating a previously unknown protective role for CHOP after prolonged hyperoxia. We conclude that hyperoxia increases CHOP expression via an ER stress-independent, PKRdependent pathway and that increased CHOP expression protects against hyperoxia-induced lung injury.CCAAT enhancer-binding protein homologous protein; acute respiratory distress syndrome; endoplasmic reticulum stress; epithelial cell; eukaryotic initiation factor-2␣; activating transcription factor-4; double-stranded RNA-activated protein kinase OXYGEN SUPPLEMENTATION is routinely used in the management of patients with acute respiratory failure. However, prolonged exposure to hyperoxia has long been recognized as a potential contributor to acute lung injury (26). In animals, prolonged exposure to hyperoxia causes lung injury, characterized by cell death, increased lung permeability, edema, and inflammation (5, 29). Although the exact mechanisms by which hyperoxia causes lung injury are incompletely understood, generation of reactive oxygen species (ROS) and cellular apoptosis appear to play important roles (1).One potential mechanism linking ROS generation and cell death is endoplasmic reticulum (ER) stress, resulting in activation of the associated unfolded protein response (UPR) (23). The ER functions to modify proteins for subsequent exposure to the extracellular environment. ER stress occurs ...

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Section: Discussionmentioning

confidence: 99%

PKR-dependent CHOP induction limits hyperoxia-induced lung injury

Lozon¹,

Eastman²,

Matute-Bello

et al. 2011

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…PA-BSA was prepared as described previously. 34 The next day, cells were treated with AICAR, BSA, or PA as described. 34 …”

Section: Cell Culture Designmentioning

confidence: 99%

AMPK Mediates the Initiation of Kidney Disease Induced by a High-Fat Diet

Declèves

Mathew

Cunard

et al. 2011

Journal of the American Society of Nephrology

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226

240

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The mechanisms underlying the association between obesity and progressive renal disease are not well understood. Exposure to a high-fat diet decreases levels of the cellular energy sensor AMPK in many organs, including the kidney, but whether AMPK contributes to the pathophysiology of kidney disease induced by a high-fat diet is unknown. In this study, we randomly assigned C57BL/6J mice to a standard or high-fat diet. After 1 week, mice fed a high-fat diet exhibited an increase in body weight, renal hypertrophy, an increase in urine H 2 O 2 and urine MCP-1, and a decrease in circulating adiponectin levels and renal AMPK activity. Urine ACR progressively increased after 4 weeks of a high-fat diet. After 12 weeks, kidneys of mice fed a high-fat diet demonstrated a marked increase in markers of fibrosis and inflammation, and AMPK activity remained significantly suppressed. To determine whether inhibition of AMPK activity explained these renal effects, we administered an AMPK activator along with a high-fat diet for 1 week. Although AMPK activation did not abrogate the weight gain, it reduced the renal hypertrophy, urine H 2 O 2 , and urine and renal MCP-1. In vitro, AMPK activation completely inhibited the induction of MCP-1 by palmitic acid in mesangial cells. In conclusion, these data suggest that the energy sensor AMPK mediates the early renal effects of a high-fat diet. Obesity has been dramatically increasing in the United States and worldwide. Between 1999 and 2004, 32.2% of all adults in the United States were obese (body mass index Ͼ 30 kg/m 2 ) 1 and the prevalence of obesity is expected to reach 50% by 2030. Obesity is the major risk factor for the metabolic syndrome, characterized by insulin resistance, dyslipidemia, and hypertension. 2 Obesity in association with insulin resistance contribute to the development of cardiovascular disease and diabetes. Furthermore, obesity is now being increasingly recognized as a major and independent risk factor for the development of kidney disease. [3][4][5] In the general population, obesity was the second most highly predictive factor to predict ESRD, even independent of diabetes and hypertension. 6 Clinical and experimental studies have demonstrated that the characteristic features of obesity-induced kidney injury include glomerular hypertrophy, thickening of the glomerular basement membrane, mesangial matrix expansion, and increased renal inflammation. [7][8][9][10] These alterations likely contribute to albuminuria, a progressive decline in renal function and ultimately glomerulosclerosis and tubulointerstitial fibrosis. 7-10 Despite the public health and clinical implications of the relationships between obesity and kidney injury, the signaling pathways leading to renal pathology with obesity are not well understood.

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“…CHOP has been documented to activate the ER oxidase, GADD34, TRB3, and the proapoptotic factors Bim and death receptor 5 while decreasing the expression of the prosurvival protein Bcl-2. [83,[86][87][88][89][90][91] This is not always the case in all cell types and some neurological diseases, e.g. murine models with Pelizaeus-Merzbacher disease.…”

Section: Thapsigargin Also Classified As a Guaianementioning

confidence: 99%

Selected terpenoids from medicinal plants modulate endoplasmic reticulum stress in metabolic disorders

Beukes

Levendal

Frost

2014

Journal of Pharmacy and Pharmacology

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Objectives The majority of research performed on cellular stress and apoptosis focuses on mitochondrial dysfunction; however, the importance of the endoplasmic reticulum dysfunction and the link to metabolic diseases has gained a substantial interest. This review focuses on the potential of terpenoids to influence endoplasmic reticulum stress and the possible role terpenoids play as the treatment of metabolic diseases. Key findings Metabolic diseases develop as a result of a cascade of cellular pathways. In most cases, cells are able to compensate for the disruption of the cellular homeostasis although the initiation of response pathways; however, chronic stress initiates apoptotic pathways. This reviewed (1) showed the importance of phytoterpenoids to influence endoplasmic reticulum (ER) stress and homeostasis, (2) showed how regulating ER stress affect the cell survival and death, and (3) highlighted some examples of how the progression of metabolic diseases can be influenced by ER. Summary Due to the substantial number of terpenoids that have been identified in literature, this review gave examples of 21 terpenoids that have been documented to have an effect on the different proteins associated with ER stress, how these plant terpenoids influence ER dysfunction and metabolic diseases such as diabetes, cancer, liver, and neurological diseases and parasitic infections.

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TRB3 is stimulated in diabetic kidneys, regulated by the ER stress marker CHOP, and is a suppressor of podocyte MCP-1

Cited by 74 publications

References 61 publications

PKR-dependent CHOP induction limits hyperoxia-induced lung injury

PKR-dependent CHOP induction limits hyperoxia-induced lung injury

AMPK Mediates the Initiation of Kidney Disease Induced by a High-Fat Diet

Selected terpenoids from medicinal plants modulate endoplasmic reticulum stress in metabolic disorders

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