Activation of the UPR Protects against Cigarette Smoke-induced RPE Apoptosis through Up-Regulation of Nrf2

Huang, Chuangxin; Wang, Joshua J.; Jacey, H.; Jin, Chenjin; Yu, Qiang; Zhang, Sarah X.

doi:10.1074/jbc.m114.603738

Cited by 66 publications

(79 citation statements)

References 55 publications

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“…Here again, CHOP, which ordinarily functions as a proapoptotic gene during ER stress, is required here for NRF2 up-regulation as recently observed in cigarette smoke-induced ROS stress experiments in ARPE-19 cells. 42 Our results also identify a NRF2 activator, Ai-1, as an effective protective compound against severe oxidative challenge. Other NRF2 activators have previously been shown to have protective effects in RPE cell lines.…”

Section: Discussionmentioning

confidence: 61%

Modeling the Dynamic AMD-Associated Chronic Oxidative Stress Changes in Human ESC and iPSC-Derived RPE Cells

Garcia

Gutierrez

Reynolds

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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Citation: Garcia TY, Gutierrez M, Reynolds J, Lamba DA. Modeling the dynamic AMD-associated chronic oxidative stress changes in human ESC and iPSC-derived RPE cells. Invest Ophthalmol Vis Sci. 2015;56:7480-7488. DOI:10.1167/iovs.15-17251 PURPOSE. Here we use human embryonic stem cells (hESCs) and human-induced pluripotent stem cell (hiPSC)-derived retinal pigment epithelium (RPE) cells to model chronic oxidative stress in vitro. This model allows us to understand the evolution of chronic stress response in RPE in vivo, as well as to monitor microRNAs changes. Finally, we use this in vitro model to identify a partial agonist of NRF2 that is protective against reactive oxygen species (ROS)-induced cytotoxicity.METHODS. The hESCs and hiPSCs were differentiated toward an RPE fate. Upon maturation, RPE cells were subjected to chronic oxidative stress using Paraquat (PQ). The cells were then analyzed using immunocytochemistry and quantitative RT-PCR to look for changes in gene expression and microRNA changes. Small molecules targeting NRF2 pathways were utilized to look for protection against oxidative stress-induced apoptosis.RESULTS. We show that 160 lM PQ can be used to generate a model of chronic oxidative stress in RPE cells derived from hESCs and hiPSCs. Using this model, we characterize the NRF2 pathway effectors during the early and late stages of chronic oxidative stress and identify microRNAs changes during oxidative stress. We find that hsa-miR144 modulates NRF2 activity during ROS stress. Lastly, we found a small molecule modulator of NRF2 that plays a protective role against oxidative stress-induced RPE apoptosis.CONCLUSIONS. In summary, pluripotent stem cell-derived retinal cells can be used to model retinal diseases in a dish. This can provide an unprecedented opportunity to understand the evolution of disease processes and allow us to identify novel therapeutics.Keywords: age-related macular degeneration, disease modeling, oxidative stress, microRNA, NRF2 A ge-related macular degeneration (AMD) is the leading cause of worldwide blindness in the elderly, affecting almost 15 million people in the United States. Retinal changes associated with AMD are present in approximately 10% of people over 65 years of age and as many as one in three people over the age of 80 years. Although the disease was first described in the 1800s, its etiology remains poorly understood, and multiple factors may be involved in the progression of the disorder, including chronic oxidative stress. A number of studies have associated oxidative stress as the key driver to AMD.1,2 The retina is one of the tissues with the greatest consumption of oxygen in the body. 3 This results in significant production of reactive oxygen species (ROS) in the retinal pigment epithelium (RPE). Increasing age results in the loss of ability to deal with this excessive ROS, which leads to oxidative damage.There are no known effective forms of treatment for the common dry form of AMD. This likely is due to the complex multifactorial etiology of AMD and...

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Section: Discussionmentioning

confidence: 61%

Modeling the Dynamic AMD-Associated Chronic Oxidative Stress Changes in Human ESC and iPSC-Derived RPE Cells

Garcia

Gutierrez

Reynolds

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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“…Our data are consistent with previous reports indicating that CSE dysregulates the UPR and suppresses XBP1s in several cell types, and that overexpression of XBP1 protects cells against CSE-induced apoptosis. 24, 35 The mechanisms underlying the inhibitory effects of smoking on XBP1s expression in acinar cells are unclear and may be related to decreases in gene transcription, XBP1 RNA stability, or inhibition of IRE1-induced XBP1 RNA splicing. In this respect, we found that acrolein, a CSE chemical that, like the IRE1-RNase inhibitor, can form Schiff bases with lysine residues and protein and DNA adducts, 22 also reduces XBP1s levels and promotes cell death.…”

Section: Discussionmentioning

confidence: 99%

The Combination of Alcohol and Cigarette Smoke Induces Endoplasmic Reticulum Stress and Cell Death in Pancreatic Acinar Cells

Lugea

Gerloff

et al. 2017

Gastroenterology

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Background & Aims Smoking, an independent risk factor for pancreatitis, accelerates the development of alcoholic pancreatitis. Alcohol feeding of mice induces upregulation of spliced X-box binding protein 1 (XBP1s), which regulates the endoplasmic reticulum (ER) unfolded protein response and promotes cell survival upon ER stress. We examined whether smoking affects the adaptive mechanisms induced by alcohol and accelerates disorders of the ER in pancreatic acinar cells. Methods We studied the combined effects of ethanol and cigarette smoke extract (CSE) on ER-stress and cell death responses in mouse and human primary acini and the acinar cell line AR42J. Cells were incubated with ethanol (EtOH, 50 mM), CSE (20–40 μg/ml), or both (CSE+EtOH), and analyzed by immunoblotting, quantitative reverse transcription PCR, and cell death assays. Some cells were incubated with MKC-3946, an inhibitor of endoplasmic reticulum to nucleus signaling 1 (ERN1, also called IRE1) that blocks XBP1s formation. Male Sprague-Dawley rats were fed isocaloric amounts of an ethanol-containing (Lieber-DeCarli) or control diet for 11 weeks and exposed to cigarette smoke or room air in an exposure chamber for 2 hours each day. During the last 3 weeks, a subset of rats received intravenous injections of lipopolysaccharide (LPS, 3 mg/kg per weeks) to induce pancreatitis or saline (control). Pancreatic tissues were collected and analyzed by histology and immunostaining techniques. Results In AR42J and primary acini, CSE+EtOH induced cell death (necrosis and apoptosis), but neither agent alone had this effect. Cell death was associated with a significant decrease in expression of XBP1s. CSE+EtOH, but neither agent alone, slightly decreased ATP levels in AR42J cells, but induced oxidative stress and sustained activation (phosphorylation) of eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3, also called PERK) and increased protein levels of DNA damage inducible transcript 3 (DDIT3, also called CHOP). CHOP regulates transcription to promote apoptosis. Incubation of AR42J or primary mouse or human acinar cells with MKC-3946 reduced expression of XBP1s, increased levels of CHOP and induced cell death. In rats fed ethanol diet, exposure to cigarette smoke increased ER stress in acinar cells and sensitized the pancreas to LPS-induced pathology. Conclusions Cigarette smoke promotes cell death and features of pancreatitis in ethanol-sensitized acinar cells by suppressing the adaptive unfolded protein response signaling pathway. It also activates ER stress pathways that promote acinar cell death.

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“…Increased NRF2 protein levels, as a consequence of oxidative stress, have been reported in vitro. Zhang's laboratory (52) showed that NRF2 levels increased in ARPE-19 cells exposed to cigarette smoke extract; levels were attenuated by treatment with N-acetylcysteine, an antioxidant. Understanding whether Sigma1R has a role in modulating antioxidant gene expression and NRF2 levels could be addressed in future studies by crossing Nrf2 −/− mice with rd10 mice in the Table S3.…”

Section: Discussionmentioning

confidence: 99%

Activation of the molecular chaperone, sigma 1 receptor, preserves cone function in a murine model of inherited retinal degeneration

Wang

Saul

Roon

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

119

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Retinal degenerative diseases are major causes of untreatable blindness, and novel approaches to treatment are being sought actively. Here we explored the activation of a unique protein, sigma 1 receptor (Sig1R), in the treatment of PRC loss because of its multifaceted role in cellular survival. We used Pde6β rd10 (rd10) mice, which harbor a mutation in the rod-specific phosphodiesterase gene Pde6β and lose rod and cone photoreceptor cells (PRC) within the first 6 wk of life, as a model for severe retinal degeneration. Systemic administration of the high-affinity Sig1R ligand (+)-pentazocine [(+)-PTZ] to rd10 mice over several weeks led to the rescue of cone function as indicated by electroretinographic recordings using natural noise stimuli and preservation of cone cells upon spectral domain optical coherence tomography and retinal histological examination. The protective effect appears to result from the activation of Sig1R, because rd10/Sig1R

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Activation of the UPR Protects against Cigarette Smoke-induced RPE Apoptosis through Up-Regulation of Nrf2

Cited by 66 publications

References 55 publications

Modeling the Dynamic AMD-Associated Chronic Oxidative Stress Changes in Human ESC and iPSC-Derived RPE Cells

Modeling the Dynamic AMD-Associated Chronic Oxidative Stress Changes in Human ESC and iPSC-Derived RPE Cells

The Combination of Alcohol and Cigarette Smoke Induces Endoplasmic Reticulum Stress and Cell Death in Pancreatic Acinar Cells

Activation of the molecular chaperone, sigma 1 receptor, preserves cone function in a murine model of inherited retinal degeneration

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