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16 pages, 2886 KiB

Open AccessArticle

The Role of the Unfolded Protein Response on Renal Lipogenesis in C57BL/6 Mice

by Elizabeth Figueroa-Juárez, Lilia G. Noriega, Carlos Pérez-Monter, Gabriela Alemán, Rogelio Hernández-Pando, Ricardo Correa-Rotter, Victoria Ramírez, Armando R. Tovar, Iván Torre-Villalvazo and Claudia Tovar-Palacio

Biomolecules 2021, 11(1), 73; https://doi.org/10.3390/biom11010073 - 7 Jan 2021

Cited by 7 | Viewed by 3556

Abstract

Renal injury observed in several pathologies has been associated with lipid accumulation in the kidney. While it has been suggested that the accumulation of renal lipids depends on free fatty acids released from adipose tissue, it is not known whether in situ renal [...] Read more.

Renal injury observed in several pathologies has been associated with lipid accumulation in the kidney. While it has been suggested that the accumulation of renal lipids depends on free fatty acids released from adipose tissue, it is not known whether in situ renal lipogenesis due to endoplasmic reticulum (ER) stress contributes to kidney injury. The aim of the present study was to elucidate the role of pharmacological ER stress in renal structure and function and its effect on renal lipid metabolism of C57BL/6 mice. ER stress increased serum creatinine and induced kidney structural abnormalities. Tunicamycin-administered mice developed hyperinsulinemia, augmented lipolysis and increased circulating leptin and adiponectin. Renal unfolded protein response (UPR) gene expression markers, the lipogenic transcription factor SREBP1 and the phosphorylation of eIF2α increased 8 h after tunicamycin administration. At 24 h, an increase in BiP protein content was accompanied by a reduction in p-eIF2α and increased SREBP-1 and FASn protein content, in addition to a significant increase in triglyceride content and a reduction in AMPK. Thus, ER stress induces in situ lipid synthesis, leading to renal lipid accumulation and functional alterations. Future pharmacological and/or dietary strategies must target renal ER stress to prevent kidney damage and the progression of metabolic diseases. Full article

(This article belongs to the Special Issue Endoplasmic Reticulum Stress in Diseases)

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15 pages, 4048 KiB

Open AccessArticle

Molecular Insights of Copper Sulfate Exposure-Induced Nephrotoxicity: Involvement of Oxidative and Endoplasmic Reticulum Stress Pathways

by Chongshan Dai, Qiangqiang Liu, Daowen Li, Gaurav Sharma, Jianli Xiong and Xilong Xiao

Biomolecules 2020, 10(7), 1010; https://doi.org/10.3390/biom10071010 - 8 Jul 2020

Cited by 25 | Viewed by 3824

Abstract

The precise pathogenic mechanism in Cu exposure-cause nephrotoxicity remains unclear. This study investigated the underlying molecular mechanism of copper sulfate (CuSO₄)-induced nephrotoxicity. Mice were treated with CuSO₄ at 50, 100, 200 mg/kg/day or co-treated with CuSO₄ (200 mg/kg/day) and [...] Read more.

The precise pathogenic mechanism in Cu exposure-cause nephrotoxicity remains unclear. This study investigated the underlying molecular mechanism of copper sulfate (CuSO₄)-induced nephrotoxicity. Mice were treated with CuSO₄ at 50, 100, 200 mg/kg/day or co-treated with CuSO₄ (200 mg/kg/day) and 4-phenylbutyric acid (4-PBA, 100 mg/kg/day) for 28 consecutive days. HEK293 cells were treated with CuSO₄ (400 μM) with or without superoxide dismutase, catalase or 4-PBA for 24 h. Results showed that CuSO₄ exposure can cause renal dysfunction and tubular necrosis in the kidney tissues of mice. CuSO₄ exposure up-regulated the activities and mRNA expression of caspases-9 and -3 as well as the expression of glucose-regulated protein 78 (GRP78), GRP94, DNA damage-inducible gene 153 (GADD153/CHOP), caspase-12 mRNAs in the kidney tissues. Furthermore, superoxide dismutase and catalase pre-treatments partly inhibited CuSO₄-induced cytotoxicity by decreasing reactive oxygen species (ROS) production, activities of caspases-9 and -3 and DNA fragmentations in HEK293 cells. 4-PBA co-treatment significantly improved CuSO₄-induced cytotoxicity in HEK293 cells and inhibited CuSO₄ exposure-induced renal dysfunction and pathology damage in the kidney tissues. In conclusion, our results reveal that oxidative stress and endoplasmic reticulum stress contribute to CuSO₄-induced nephrotoxicity. Our study highlights that targeting endoplasmic reticulum and oxidative stress may offer an approach for Cu overload-caused nephrotoxicity. Full article

(This article belongs to the Special Issue Endoplasmic Reticulum Stress in Diseases)

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13 pages, 2949 KiB

Open AccessArticle

TGF-β1 Activates Nasal Fibroblasts through the Induction of Endoplasmic Reticulum Stress

by Jae-Min Shin, Ju-Hyung Kang, Joo-Hoo Park, Hyun-Woo Yang, Heung-Man Lee and Il-Ho Park

Biomolecules 2020, 10(6), 942; https://doi.org/10.3390/biom10060942 - 22 Jun 2020

Cited by 8 | Viewed by 2843

Abstract

(1) Background: Tissue remodeling and extracellular matrix (ECM) accumulation contribute to the development of chronic inflammatory diseases of the upper airway. Endoplasmic reticulum (ER) stress is considered to be the key signal for triggering tissue remodeling in pathological conditions. The present study aimed [...] Read more.

(1) Background: Tissue remodeling and extracellular matrix (ECM) accumulation contribute to the development of chronic inflammatory diseases of the upper airway. Endoplasmic reticulum (ER) stress is considered to be the key signal for triggering tissue remodeling in pathological conditions. The present study aimed to investigate the role of ER-stress in TGF-β1-stimulated nasal fibroblasts and inferior turbinate organ cultures; (2) Methods: Fibroblasts and organ cultures were pretreated with 4-phenylbutyric acid (PBA) and stimulated with TGF-β1 or thapsigargin (TG). Expression of ER-stress markers, myofibroblast marker, and ECM components was measured by Western blotting and real-time PCR. Reactive oxygen species (ROS) were quantified using 2′,7′-dichlorofluorescein diacetate. Cell migration was evaluated using Transwell assays. Contractile activity was measured by collagen contraction assay; (3) Results: 4-PBA inhibited TGF-β1 or TG-induced ER-stress marker expression, phenotypic changes, and ECM. Pre-treatment with ROS scavengers inhibited the expression of TGF-β1-induced ER-stress markers. Migration and collagen contraction of TGF-β1 or TG-stimulated fibroblasts were ameliorated by 4-PBA treatment. These findings were confirmed in ex vivo organ cultures; (4) Conclusions: 4-PBA downregulates TGF-β1-induced ER-stress marker expression, migration, and collagen contraction via ROS in fibroblasts and organ cultures. These results suggest that ER-stress may play an important role in progression of chronic upper airway inflammatory diseases by aiding pathological tissue remodeling. Full article

(This article belongs to the Special Issue Endoplasmic Reticulum Stress in Diseases)

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Review

Jump to: Research

21 pages, 2967 KiB

Open AccessFeature PaperReview

PERK Pathway and Neurodegenerative Disease: To Inhibit or to Activate?

by Talya Shacham, Chaitanya Patel and Gerardo Z. Lederkremer

Biomolecules 2021, 11(3), 354; https://doi.org/10.3390/biom11030354 - 26 Feb 2021

Cited by 39 | Viewed by 6593

Abstract

With the extension of life span in recent decades, there is an increasing burden of late-onset neurodegenerative diseases, for which effective treatments are lacking. Neurodegenerative diseases include the widespread Alzheimer’s disease (AD) and Parkinson’s disease (PD), the less frequent Huntington’s disease (HD) and [...] Read more.

With the extension of life span in recent decades, there is an increasing burden of late-onset neurodegenerative diseases, for which effective treatments are lacking. Neurodegenerative diseases include the widespread Alzheimer’s disease (AD) and Parkinson’s disease (PD), the less frequent Huntington’s disease (HD) and Amyotrophic Lateral Sclerosis (ALS) and also rare early-onset diseases linked to mutations that cause protein aggregation or loss of function in genes that maintain protein homeostasis. The difficulties in applying gene therapy approaches to tackle these diseases is drawing increasing attention to strategies that aim to inhibit cellular toxicity and restore homeostasis by intervening in cellular pathways. These include the unfolded protein response (UPR), activated in response to endoplasmic reticulum (ER) stress, a cellular affliction that is shared by these diseases. Special focus is turned to the PKR-like ER kinase (PERK) pathway of the UPR as a target for intervention. However, the complexity of the pathway and its ability to promote cell survival or death, depending on ER stress resolution, has led to some confusion in conflicting studies. Both inhibition and activation of the PERK pathway have been reported to be beneficial in disease models, although there are also some reports where they are counterproductive. Although with the current knowledge a definitive answer cannot be given on whether it is better to activate or to inhibit the pathway, the most encouraging strategies appear to rely on boosting some steps without compromising downstream recovery. Full article

(This article belongs to the Special Issue Endoplasmic Reticulum Stress in Diseases)

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15 pages, 1065 KiB

Open AccessReview

Signaling Nodes Associated with Endoplasmic Reticulum Stress during NAFLD Progression

by Ja Hyun Koo and Chang Yeob Han

Biomolecules 2021, 11(2), 242; https://doi.org/10.3390/biom11020242 - 8 Feb 2021

Cited by 22 | Viewed by 4066

Abstract

Excess and sustained endoplasmic reticulum (ER) stress, paired with a failure of initial adaptive responses, acts as a critical trigger of nonalcoholic fatty liver disease (NAFLD) progression. Unfortunately, there is no drug currently approved for treatment, and the molecular basis of pathogenesis by [...] Read more.

Excess and sustained endoplasmic reticulum (ER) stress, paired with a failure of initial adaptive responses, acts as a critical trigger of nonalcoholic fatty liver disease (NAFLD) progression. Unfortunately, there is no drug currently approved for treatment, and the molecular basis of pathogenesis by ER stress remains poorly understood. Classical ER stress pathway molecules have distinct but inter-connected functions and complicated effects at each phase of the disease. Identification of the specific molecular signal mediators of the ER stress-mediated pathogenesis is, therefore, a crucial step in the development of new treatments. These signaling nodes may be specific to the cell type and/or the phase of disease progression. In this review, we highlight the recent advancements in knowledge concerning signaling nodes associated with ER stress and NAFLD progression in various types of liver cells. Full article

(This article belongs to the Special Issue Endoplasmic Reticulum Stress in Diseases)

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33 pages, 1982 KiB

Open AccessFeature PaperReview

ER Stress and Unfolded Protein Response in Leukemia: Friend, Foe, or Both?

by Kelly Féral, Manon Jaud, Céline Philippe, Doriana Di Bella, Stéphane Pyronnet, Kevin Rouault-Pierre, Laurent Mazzolini and Christian Touriol

Biomolecules 2021, 11(2), 199; https://doi.org/10.3390/biom11020199 - 30 Jan 2021

Cited by 21 | Viewed by 5648

Abstract

The unfolded protein response (UPR) is an evolutionarily conserved adaptive signaling pathway triggered by a stress of the endoplasmic reticulum (ER) lumen compartment, which is initiated by the accumulation of unfolded proteins. This response, mediated by three sensors-Inositol Requiring Enzyme 1 (IRE1), Activating [...] Read more.

The unfolded protein response (UPR) is an evolutionarily conserved adaptive signaling pathway triggered by a stress of the endoplasmic reticulum (ER) lumen compartment, which is initiated by the accumulation of unfolded proteins. This response, mediated by three sensors-Inositol Requiring Enzyme 1 (IRE1), Activating Transcription Factor 6 (ATF6), and Protein Kinase RNA-Like Endoplasmic Reticulum Kinase (PERK)—allows restoring protein homeostasis and maintaining cell survival. UPR represents a major cytoprotective signaling network for cancer cells, which frequently experience disturbed proteostasis owing to their rapid proliferation in an usually unfavorable microenvironment. Increased basal UPR also participates in the resistance of tumor cells against chemotherapy. UPR activation also occurs during hematopoiesis, and growing evidence supports the critical cytoprotective role played by ER stress in the emergence and proliferation of leukemic cells. In case of severe or prolonged stress, pro-survival UPR may however evolve into a cell death program called terminal UPR. Interestingly, a large number of studies have revealed that the induction of proapoptotic UPR can also strongly contribute to the sensitization of leukemic cells to chemotherapy. Here, we review the current knowledge on the consequences of the deregulation of UPR signaling in leukemias and their implications for the treatment of these diseases. Full article

(This article belongs to the Special Issue Endoplasmic Reticulum Stress in Diseases)

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31 pages, 1115 KiB

Open AccessReview

ER Stress-Sensor Proteins and ER-Mitochondrial Crosstalk—Signaling Beyond (ER) Stress Response

by Vaishali Kumar and Shuvadeep Maity

Biomolecules 2021, 11(2), 173; https://doi.org/10.3390/biom11020173 - 28 Jan 2021

Cited by 52 | Viewed by 7515

Abstract

Recent studies undoubtedly show the importance of inter organellar connections to maintain cellular homeostasis. In normal physiological conditions or in the presence of cellular and environmental stress, each organelle responds alone or in coordination to maintain cellular function. The Endoplasmic reticulum (ER) and [...] Read more.

Recent studies undoubtedly show the importance of inter organellar connections to maintain cellular homeostasis. In normal physiological conditions or in the presence of cellular and environmental stress, each organelle responds alone or in coordination to maintain cellular function. The Endoplasmic reticulum (ER) and mitochondria are two important organelles with very specialized structural and functional properties. These two organelles are physically connected through very specialized proteins in the region called the mitochondria-associated ER membrane (MAM). The molecular foundation of this relationship is complex and involves not only ion homeostasis through the shuttling of calcium but also many structural and apoptotic proteins. IRE1alpha and PERK are known for their canonical function as an ER stress sensor controlling unfolded protein response during ER stress. The presence of these transmembrane proteins at the MAM indicates its potential involvement in other biological functions beyond ER stress signaling. Many recent studies have now focused on the non-canonical function of these sensors. In this review, we will focus on ER mitochondrial interdependence with special emphasis on the non-canonical role of ER stress sensors beyond ER stress. Full article

(This article belongs to the Special Issue Endoplasmic Reticulum Stress in Diseases)

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22 pages, 1068 KiB

Open AccessReview

The UPR in Neurodegenerative Disease: Not Just an Inside Job

by Anna Maria van Ziel and Wiep Scheper

Biomolecules 2020, 10(8), 1090; https://doi.org/10.3390/biom10081090 - 22 Jul 2020

Cited by 17 | Viewed by 3641

Abstract

Neurons are highly specialized cells that continuously and extensively communicate with other neurons, as well as glia cells. During their long lifetime, the post-mitotic neurons encounter many stressful situations that can disrupt protein homeostasis (proteostasis). The importance of tight protein quality control is [...] Read more.

Neurons are highly specialized cells that continuously and extensively communicate with other neurons, as well as glia cells. During their long lifetime, the post-mitotic neurons encounter many stressful situations that can disrupt protein homeostasis (proteostasis). The importance of tight protein quality control is illustrated by neurodegenerative disorders where disturbed neuronal proteostasis causes neuronal dysfunction and loss. For their unique function, neurons require regulated and long-distance transport of membrane-bound cargo and organelles. This highlights the importance of protein quality control in the neuronal endomembrane system, to which the unfolded protein response (UPR) is instrumental. The UPR is a highly conserved stress response that is present in all eukaryotes. However, recent studies demonstrate the existence of cell-type-specific aspects of the UPR, as well as cell non-autonomous UPR signaling. Here we discuss these novel insights in view of the complex cellular architecture of the brain and the implications for neurodegenerative diseases. Full article

(This article belongs to the Special Issue Endoplasmic Reticulum Stress in Diseases)

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16 pages, 2786 KiB

Open AccessReview

The S100B Protein and Partners in Adipocyte Response to Cold Stress and Adaptive Thermogenesis: Facts, Hypotheses, and Perspectives

by Jacques Baudier and Benoit J Gentil

Biomolecules 2020, 10(6), 843; https://doi.org/10.3390/biom10060843 - 31 May 2020

Cited by 12 | Viewed by 3949

Abstract

In mammals, adipose tissue is an active secretory tissue that responds to mild hypothermia and as such is a genuine model to study molecular and cellular adaptive responses to cold-stress. A recent study identified a mammal-specific protein of the endoplasmic reticulum that is [...] Read more.

In mammals, adipose tissue is an active secretory tissue that responds to mild hypothermia and as such is a genuine model to study molecular and cellular adaptive responses to cold-stress. A recent study identified a mammal-specific protein of the endoplasmic reticulum that is strongly induced in the inguinal subcutaneous white adipocyte upon exposure to cold, calsyntenin 3β (CLSTN3β). CLSTN3β regulates sympathetic innervation of thermogenic adipocytes and contributes to adaptive non-shivering thermogenesis. The calcium- and zinc-binding S100B is a downstream effector in the CLSTN3β pathways. We review, here, the literature on the transcriptional regulation of the S100b gene in adipocyte cells. We also rationalize the interactions of the S100B protein with its recognized or hypothesized intracellular (p53, ATAD3A, CYP2E1, AHNAK) and extracellular (Receptor for Advanced Glycation End products (RAGE), RPTPσ) target proteins in the context of adipocyte differentiation and adaptive thermogenesis. We highlight a chaperon-associated function for the intracellular S100B and point to functional synergies between the different intracellular S100B target proteins. A model of non-classical S100B secretion involving AHNAK/S100A10/annexin2-dependent exocytosis by the mean of exosomes is also proposed. Implications for related areas of research are noted and suggestions for future research are offered. Full article

(This article belongs to the Special Issue Endoplasmic Reticulum Stress in Diseases)

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