Melatonin Improves Endoplasmic Reticulum Stress-Mediated IRE1α Pathway in Zücker Diabetic Fatty Rat

Obesity and diabetes are linked to an increased prevalence of kidney disease. Endoplasmic reticulum stress has recently gained growing importance in the pathogenesis of obesity and diabetes-related kidney disease. Melatonin, is an important anti-obesogenic natural bioactive compound. Previously, our research group showed that the renoprotective effect of melatonin administration was associated with restoring mitochondrial fission/fusion balance and function in a rat model of diabesity-induced kidney injury. This study was carried out to further investigate whether melatonin could suppress renal endoplasmic reticulum (ER) stress response and the downstream unfolded protein response activation under obese and diabetic conditions. Zücker diabetic fatty (ZDF) rats and lean littermates (ZL) were orally supplemented either with melatonin (10 mg/kg body weight (BW)/day) (M–ZDF and M–ZL) or vehicle (C–ZDF and C–ZL) for 17 weeks. Western blot analysis of ER stress-related markers and renal morphology were assessed. Compared to C–ZL rats, higher ER stress response associated with impaired renal morphology was observed in C–ZDF rats. Melatonin supplementation alleviated renal ER stress response in ZDF rats, by decreasing glucose-regulated protein 78 (GRP78), phosphoinositol-requiring enzyme1α (IRE1α), and ATF6 levels but had no effect on phospho–protein kinase RNA–like endoplasmic reticulum kinase (PERK) level. In addition, melatonin supplementation also restrained the ER stress-mediated apoptotic pathway, as indicated by decreased pro-apoptotic proteins phospho–c–jun amino terminal kinase (JNK), Bax, and cleaved caspase-3, as well as by upregulation of B cell lymphoma (Bcl)-2 protein. These improvements were associated with renal structural recovery. Taken together, our findings revealed that melatonin play a renoprotective role, at least in part, by suppressing ER stress and related pro-apoptotic IRE1α/JNK signaling pathway.

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NOD1/NOD2 and RIP2 Regulate Endoplasmic Reticulum Stress-Induced Inflammation during Chlamydia Infection

mBio ◽

10.1128/mbio.00979-20 ◽

2020 ◽

Vol 11 (3) ◽

Author(s):

Oanh H. Pham ◽

Bokyung Lee ◽

Jasmine Labuda ◽

A. Marijke Keestra-Gounder ◽

Mariana X. Byndloss ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Stress Response ◽

Inflammatory Response ◽

Endoplasmic Reticulum Stress ◽

Er Stress ◽

Young Women ◽

The United States ◽

Chlamydia Infection ◽

Er Stress Response

ABSTRACT The inflammatory response to Chlamydia infection is likely to be multifactorial and involve a variety of ligand-dependent and -independent recognition pathways. We previously reported the presence of NOD1/NOD2-dependent endoplasmic reticulum (ER) stress-induced inflammation during Chlamydia muridarum infection in vitro, but the relevance of this finding to an in vivo context is unclear. Here, we examined the ER stress response to in vivo Chlamydia infection. The induction of interleukin 6 (IL-6) production after systemic Chlamydia infection correlated with expression of ER stress response genes. Furthermore, when tauroursodeoxycholate (TUDCA) was used to inhibit the ER stress response, an increased bacterial burden was detected, suggesting that ER stress-driven inflammation can contribute to systemic bacterial clearance. Mice lacking both NOD1 and NOD2 or RIP2 exhibited slightly higher systemic bacterial burdens after infection with Chlamydia. Overall, these data suggest a model where RIP2 and NOD1/NOD2 proteins link ER stress responses with the induction of Chlamydia-specific inflammatory responses. IMPORTANCE Understanding the initiation of the inflammatory response during Chlamydia infection is of public health importance given the impact of this disease on young women in the United States. Many young women are chronically infected with Chlamydia but are asymptomatic and therefore do not seek treatment, leaving them at risk of long-term reproductive harm due to inflammation in response to infection. Our manuscript explores the role of the endoplasmic reticulum stress response pathway initiated by an innate receptor in the development of this inflammation.

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ER Stress Response Failure and Steatohepatitis Comorbid with Diabetes

10.5772/intechopen.100054 ◽

2021 ◽

Author(s):

Takayoshi Sasako ◽

Kohjiro Ueki

Keyword(s):

Insulin Resistance ◽

Endoplasmic Reticulum ◽

Stress Response ◽

Er Stress ◽

Hepatic Insulin Resistance ◽

Diabetic Patients ◽

Stress Induction ◽

Er Stress Response ◽

Glucose And Lipid Metabolism ◽

Obesity And Diabetes

Dynamic metabolic changes occur in the liver during the transition between fasting and eating, which is mainly mediated by insulin, a hormone to promote anabolism and suppress catabolism. In obesity and diabetes, insulin resistance is induced via various mechanisms, and among them is endoplasmic reticulum (ER) stress. We recently reported that eating induces transient ER stress and consequent ER stress response in the liver. During eating, expression of Sdf2l1, an ER-resident molecule involved in ER stress-associated degradation, is induced as a part of ER stress response. XBP-1s regulates expression of Sdf2l1 at the transcription level, and Sdf2l1 terminates eating-induced ER stress in the liver, consequently regulating glucose and lipid metabolism. In obesity and diabetes, however, ER stress response is impaired, partly because insulin-mediated translocation of XBP-1s to the nucleus is suppressed, which results in further excessive ER stress. Induction of Sdf2l1 by XBP-1s is highly down-regulated, but restoration of Sdf2l1 ameliorates glucose intolerance and fatty liver. In diabetic patients, hepatic insulin resistance induces enhanced ER stress and ER stress response failure in the liver, which in turn promote hepatic fibrosis and contribute to the development of steatohepatitis comorbid with diabetes.

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CD125-Expressing Myeloma: A Subgroup of Multiple Myeloma (MM) with Immature Phenotype, Endoplasmic Reticulum Stress Response and Low Sensitivity to Bortezomib

Blood ◽

10.1182/blood.v116.21.616.616 ◽

2010 ◽

Vol 116 (21) ◽

pp. 616-616

Author(s):

Yawara Kawano ◽

Yoshitaka Kikukawa ◽

Miki Nakamura ◽

Yutaka Okuno ◽

Hiromichi Yuki ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Stress Response ◽

Endoplasmic Reticulum Stress ◽

Er Stress ◽

Surface Antigen ◽

High Expression ◽

Expression Level ◽

Er Stress Response ◽

The Mean ◽

Low Sensitivity

Abstract Abstract 616 Introduction Although marked heterogeneity in phenotypes of MM is known, classification of MM based on molecular expressions remains to be determined. During analysis of microarray data utilizing purified MM cells obtained from bortezomib-sensitive and resistant cases, we identified a 100-fold higher expression of CD125 in bortezomib-resistant MM cells. Because CD125, also known as interleukin-5 receptor alpha chain, is expressed on mature B cells undergoing class switch recombination, the existence of CD125 in MM cells may suggest that MM cells are at a less mature differentiation stage than plasma cells. We further tried to classify MM patients by analyzing correlations of CD125-expressions with other surface antigen expressions and endoplasmic reticulum stress (ER stress) response: the latter plays a crucial role in resistance to bortezomib. Correlation of CD125 expression with sensitivity to bortezomib therapy was also evaluated. Materials and Methods Bone marrow samples were obtained from MM patients under written informed consentaccording to Helsinki Declaration and processed for purification using CD138 immunomagnetic beads. Expressions of CD125 and spliced-XBP-1 (spliced-XBP-1 presence is a hallmark of activated ER stress response), were evaluated using real time PCR. Flowcytometry analysis was performed using gating CD38 bright population at SRL laboratory Inc. (Tokushima, Japan). Response to bortezomib was assessed according to the international myeloma working group criteria. Results CD125 expression was found in MM cells at various levels. When it was compared to other surface antigen expressions, MM cells with expression of CD125 tend to express both CD20 and CD45 (p<0.05). Expression of CD125 also correlated with high expression levels of XBP-1s (Figure 1, p<0.01). The mean expression level of CD125 in bortezomib resistant cases was 6.17 fold greater than that in sensitive cases (110.6 versus 17.9, respectively, p<0.05). The mean expression level of XBP-1s in bortezomib-resistant cases was 2.3-fold greater than that in sensitive cases (p=0.06), which might suggest a role of ER stress in the regulation of sensitivity to bortezomib, while further detailed study should be required. Conclusions The present results suggest that CD125-expression in MM may represent a distinctive disease marker, which features immature phenotype, high ER stress response, and low sensitivity to bortezomib. High expression of XBP-1s in bortezomib-resistant cases suggests that the existence of ER stress response prior to bortezomib exposure may be responsible for poor response to bortezomib. Further analysis of CD125-positive MM cells is important for clarifying tumorigenesis at early stages of B-cell differentiation and possibly developing a new therapeutic strategy targeting ER stress. Disclosures: No relevant conflicts of interest to declare.

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The endoplasmic reticulum stress response and diabetic kidney disease

AJP Renal Physiology ◽

10.1152/ajprenal.00021.2011 ◽

2011 ◽

Vol 300 (5) ◽

pp. F1054-F1061 ◽

Cited By ~ 86

Author(s):

Robyn Cunard ◽

Kumar Sharma

Keyword(s):

Endoplasmic Reticulum ◽

Stress Response ◽

Kidney Disease ◽

Er Stress ◽

Diabetic Kidney Disease ◽

Protein Translation ◽

Renal Diseases ◽

Unfolded Proteins ◽

Diabetic Kidney ◽

Er Stress Response

The endoplasmic reticulum (ER) folds and modifies proteins; however, during conditions of cellular stress, unfolded proteins accumulate in the ER and activate the unfolded protein response (UPR). The UPR, also referred to as the ER stress response, activates three distinct signaling cascades that are designed to globally reduce transcription and translation. The three major arms of the mammalian UPR include 1) protein kinase RNA (PKR)-like ER kinase (PERK), 2) inositol-requiring protein-1 (IRE1α), and 3) activating transcription factor-6 (ATF6) pathways. The PERK pathway rapidly attenuates protein translation, whereas the ATF6 and IRE1α cascades transcriptionally upregulate ER chaperone genes that promote proper folding and ER-associated degradation (ERAD) of proteins. This integrated response in turn allows the folding machinery of the ER to catch up with the backlog of unfolded proteins. The ER stress response plays a role in a number of pathophysiological processes, including pancreatic β-cell failure and apoptosis. The goals of the current review are to familiarize investigators with cellular and tissue activation of this response in the rodent and human diabetic kidney. Additionally, we will review therapeutic modulators of the ER stress response and discuss their efficacy in models of diabetic kidney disease. The ER stress response has both protective and deleterious features. A better understanding of the molecular pathways regulated during this process in a cell- and disease-specific manner could reveal novel therapeutic strategies in chronic renal diseases, including diabetic kidney disease.

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Endoplasmic Reticulum (ER) Stress Response Failure in Diseases

Trends in Cell Biology ◽

10.1016/j.tcb.2020.05.004 ◽

2020 ◽

Vol 30 (9) ◽

pp. 672-675 ◽

Cited By ~ 2

Author(s):

Kashi Raj Bhattarai ◽

Manoj Chaudhary ◽

Hyung-Ryong Kim ◽

Han-Jung Chae

Keyword(s):

Endoplasmic Reticulum ◽

Stress Response ◽

Er Stress ◽

Er Stress Response

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Ubiquitin-recognition protein Ufd1 couples the endoplasmic reticulum (ER) stress response to cell cycle control

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1100028108 ◽

2011 ◽

Vol 108 (22) ◽

pp. 9119-9124 ◽

Cited By ~ 37

Author(s):

M. Chen ◽

G. J. Gutierrez ◽

Z. A. Ronai

Keyword(s):

Cell Cycle ◽

Endoplasmic Reticulum ◽

Stress Response ◽

Er Stress ◽

Cell Cycle Control ◽

Er Stress Response ◽

Recognition Protein

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Endoplasmic reticulum stress response in the roadway for the effects of non-steroidal anti-inflammatory drugs

Endoplasmic Reticulum Stress in Diseases ◽

10.1515/ersc-2015-0001 ◽

2015 ◽

Vol 2 (1) ◽

Cited By ~ 1

Author(s):

Fernanda L.B. Mügge ◽

Aristóbolo M. Silva

Keyword(s):

Endoplasmic Reticulum ◽

Stress Response ◽

Er Stress ◽

Stress Responses ◽

Endoplasmic Reticulum Stress Response ◽

The Road ◽

Er Stress Response ◽

Mediated Effects ◽

Inflammatory Drugs ◽

Anti Inflammatory

AbstractOver the past decade, a handful of evidence has been provided that nonsteroidal anti-inflammatory drugs (NSAIDs) display effects on the homeostasis of the endoplasmic reticulum (ER). Their uptake into cells will eventually lead to activation or inhibition of key molecules that mediate ER stress responses, raising not only a growing interest for a pharmacological target in ER stress responses but also important questions how the ER-stress mediated effects induced by NSAIDs could be therapeutically advantageous or not. We review here the toxicity effects and therapeutic applications of NSAIDs involving the three majors ER stress arms namely PERK, IRE1, and ATF6. First, we provide brief introduction on the well-established and characterized downstream events mediated by these ER stress players, followed by presentation of the NSAIDs compounds and mode of action, and finally their effects on ER stress response. NSAIDs present promising drug agents targeting the components of ER stress in different aspects of cancer and other diseases, but a better comprehension of the mechanisms underlying their benefits and harms will certainly pave the road for several diseases’ therapy.

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