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Datta A, Patale P, Ghosh D, Jagtap P, Shah J, Katamneni M, Kumari A, Malik N, Karmarkar G, Barik A, Ghosh B, Dhakne P, Pathulothu V, Sarmah D, Kaur H, Rana N, Rathod R, Borah A, Sengupta P, Bhattacharya P. Modulation of Sel1L can alleviate altered ER homeostasis towards white matter damage in CKD-stroke complex. Commun Biol 2025; 8:677. [PMID: 40301526 PMCID: PMC12041469 DOI: 10.1038/s42003-025-08100-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 04/16/2025] [Indexed: 05/01/2025] Open
Abstract
Stroke is one of the major causes of mortality and long-term disability worldwide. Chronic-kidney-disease (CKD) is a condition where patients have shown increased vulnerability to stroke with poor functional and cognitive outcomes. Impaired cerebral autoregulation in CKD patients may impose a high risk of stroke. To date, the mechanism of worsened stroke outcomes in CKD patients are limitedly understood. Alterations of endoplasmic-reticulum (ER) homoeostasis via modification of Sel1L-Hrd1 complex is one of the many cellular events that gets triggered following both CKD and stroke leading to accumulation of misfolded proteins, culminating in ER-stress. Therefore, the present study aims to explore the involvement of Sel1L mediated altered ER functions towards worsening of stroke outcome in CKD and further its crucial role towards white matter damage. CKD-stroke complex was induced in male Sprague-Dawley rats followed by middle-cerebral-artery occlusion. At 24 h and 7th day of reperfusion, animals were subjected to behavioral analysis followed by euthanasia, brain harvest and molecular studies. CKD-Stroke-complex animals showed aggravated neurofunctional and cognitive impairment which were further normalized by treatment of an ER-stress inhibitor. This indicates exacerbated stroke outcome in CKD-stroke-complex may be mediated by imbalanced ER-homeostasis due to decreased Sel1L expression leading to enhanced cellular death and neurodegeneration.
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Affiliation(s)
- Aishika Datta
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, India
| | - Priti Patale
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, India
| | - Debarati Ghosh
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, India
| | - Priya Jagtap
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, India
| | - Jinagna Shah
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, India
| | - Mounika Katamneni
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, India
| | - Anita Kumari
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, India
| | - Nikita Malik
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, India
| | - Gautam Karmarkar
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, India
| | - Anirban Barik
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, India
| | - Bijoyani Ghosh
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, India
| | - Pooja Dhakne
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, India
| | - Vinod Pathulothu
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, India
| | - Deepaneeta Sarmah
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, India
| | - Harpreet Kaur
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, India
| | - Nikita Rana
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, India
| | - Rajeshwari Rathod
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, India
| | - Anupom Borah
- Cellular and Molecular Neurobiology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar, Assam, India
| | - Pinaki Sengupta
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, India
| | - Pallab Bhattacharya
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, India.
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Pushpakumar S, Juin SK, Almarshood H, Gondim DD, Ouseph R, Sen U. Diallyl Trisulfide Attenuates Ischemia-Reperfusion-Induced ER Stress and Kidney Dysfunction in Aged Female Mice. Cells 2025; 14:420. [PMID: 40136669 PMCID: PMC11941362 DOI: 10.3390/cells14060420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 03/06/2025] [Accepted: 03/07/2025] [Indexed: 03/27/2025] Open
Abstract
Ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury (AKI) in the aging population. Gender studies show that aging is associated with loss of protection from AKI in the female population. While ER stress contributes to IRI-induced AKI in the young, ER regulation during IR in the aged kidney is unclear. Because current evidence suggests hydrogen sulfide (H2S) modulates ER stress, we investigated whether exogenous supplementation of diallyl trisulfide (DATS), an H2S donor, mitigates AKI in aged female kidneys. Wild-type (WT, C57BL/6J) mice aged 75-78 weeks were treated with or without DATS before and after renal IRI. IRI increased ER stress proteins, inflammation, and fibrosis markers in the IRI kidney compared to the control. DATS mitigated ER stress, and reduced inflammation and fibrosis markers in the IRI kidney. Further, IRI kidneys demonstrated reduced blood flow, vascularity, angiogenesis, increased resistive index (RI), and reduced function. DATS treatment upregulated PI3K, AKT, p-mTOR, and pMAPK signaling to stimulate angiogenesis, which improved vascular density, blood flow, and renal function. Together, our results suggest that DATS rescues the aged female kidney IRI by modulating ER stress and upregulation of angiogenesis.
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Affiliation(s)
- Sathnur Pushpakumar
- Department of Physiology, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Subir Kumar Juin
- Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY 40202, USA;
| | - Hebah Almarshood
- Department of Physiology, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Dibson Dibe Gondim
- Department of Pathology, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Rosemary Ouseph
- Division of Nephrology & Hypertension, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Utpal Sen
- Department of Physiology, University of Louisville School of Medicine, Louisville, KY 40202, USA
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Minjares M, Thepsuwan P, Zhang K, Wang JM. Unfolded protein responses: Dynamic machinery in wound healing. Pharmacol Ther 2025; 267:108798. [PMID: 39826569 PMCID: PMC11881203 DOI: 10.1016/j.pharmthera.2025.108798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 12/11/2024] [Accepted: 01/10/2025] [Indexed: 01/22/2025]
Abstract
Skin wound healing is a dynamic process consisting of multiple cellular and molecular events that must be tightly coordinated to repair the injured tissue efficiently. The healing pace is decided by the type of injuries, the depth and size of the wounds, and whether wound infections occur. However, aging, comorbidities, genetic factors, hormones, and nutrition also impact healing outcomes. During wound healing, cells undergo robust processes of synthesizing new proteins and degrading multifunctional proteins. This imposes an increasing burden on the endoplasmic reticulum (ER), causing ER stress. Unfolded protein response (UPR) represents a collection of highly conserved stress signaling pathways originated from the ER to maintain protein homeostasis and modulate cell physiology. UPR is known to be beneficial for tissue healing. However, when excessive ER stress exceeds ER's folding potential, UPR pathways trigger cell apoptosis, interrupting tissue regeneration. Understanding how UPR pathways modulate the skin's response to injuries is critical for new interventions toward the control of acute and chronic wounds. Herein, in this review, we focus on the participation of the canonical and noncanonical UPR pathways during different stages of wound healing, summarize the available evidence demonstrating UPR's unique position in balancing homeostasis and pathophysiology of healing tissues, and highlight the understudied areas where therapeutic opportunities may arise.
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Affiliation(s)
- Morgan Minjares
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, USA
| | | | - Kezhong Zhang
- Centers for Molecular Medicine and Genetics, Wayne State University, USA; Department of Biochemistry, Microbiology, and Immunology, Wayne State University, Detroit, MI, USA.
| | - Jie-Mei Wang
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, USA; Centers for Molecular Medicine and Genetics, Wayne State University, USA; Karmanos Cancer Institute, Detroit, MI, USA.
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Younis D, Shemies R, Zakaria MM, Omar SA, Mosbah A, El-Kannishy G, Sabry A, Elnagar S. Urinary congophilia as a predictive biomarker of lupus nephritis in pregnant and non-pregnant women with systemic lupus erythematosus. Lupus 2025; 34:149-156. [PMID: 39749775 DOI: 10.1177/09612033241312746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
BACKGROUND Endoplasmic reticulum stress with protein misfolding has been introduced as a key pathogenetic mechanism in lupus nephritis (LN). Pregnancy is thought to exaggerate proteostasis, which leads to the accumulation of potentially pathogenic misfolded proteins in the urine, serum, and placenta particularly in women with preeclampsia. The detection of misfolded proteins is made using Congo red stain, which is referred to as congophilia. This study aimed to assess the predictive value of urinary congophilia as a marker of LN activity in pregnant and non-pregnant LN women. METHODS Urine samples from non-pregnant LN women (n = 45), pregnant LN women (n = 12), as well as pregnant healthy controls (n = 38) were collected. Urinary congophilia was assessed by Congo Red Dot Blot assay. The disease activity was defined according to SLE Disease Activity Index (SLEDAI) score, and SLE Disease Activity Index-Renal Domain (SLEDAI-R) score. Renal biopsy was done for 33 non-pregnant LN women as it was clinically indicated, and modified NIH activity index (AI) was assessed according to the classification of LN by the International Society of Nephrology/Renal Pathology Society (ISN/RPS). RESULTS Congo red retention (CRR) values were significantly higher for pregnant active LN patients, in comparison with pregnant inactive LN patients (p = .014), as well as pregnant healthy controls (p = .009). Additionally, CRR values were significantly higher for non-pregnant active LN patients, in comparison with non-pregnant inactive LN patients (p = .016), as well as pregnant healthy controls (p ≤ .001). There were significant positive correlations between CRR on one hand, and anti-ds-DNA (r = 0.791, p ≤ .001), serum creatinine (r = 0.620, p ≤ .001), SLEDAI score (r = 0.623, p ≤ .001), as well as SLEDAI-R score (r = 0.473, p = .005) on the other hand. A highly significant negative correlation was detected between CRR, and serum albumin (r = -0.454, p = .001). CRR at a cut point ≥21.85 had 83% sensitivity, and 58% specificity to capture high LN activity status (NIH-AI >10) versus lower LN activity status. CONCLUSION Urinary congophilia may add a diagnostic value in patients with LN and can be a reliable marker of disease activity. CRR is related to disease activity rather than pregnancy.
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Affiliation(s)
- Dalia Younis
- Mansoura Nephrology and Dialysis Unit, Mansoura University, Mansoura, Egypt
| | - Rasha Shemies
- Mansoura Nephrology and Dialysis Unit, Mansoura University, Mansoura, Egypt
| | - Mahmoud M Zakaria
- Mansoura Urology and Nephrology Center, Mansoura University, Mansoura, Egypt
| | - Sameha A Omar
- Mansoura Urology and Nephrology Center, Mansoura University, Mansoura, Egypt
| | - Alaa Mosbah
- Obstetrics and Gynecology Departments, Mansoura University, Mansoura, Egypt
| | - Ghada El-Kannishy
- Mansoura Nephrology and Dialysis Unit, Mansoura University, Mansoura, Egypt
| | - Alaa Sabry
- Mansoura Nephrology and Dialysis Unit, Mansoura University, Mansoura, Egypt
| | - Sherouk Elnagar
- Mansoura Nephrology and Dialysis Unit, Mansoura University, Mansoura, Egypt
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Yang AY, Kim JY, Gwon MG, Kwon HH, Leem J, Jeon EJ. Protective Effects of Tormentic Acid on Unilateral Ureteral Obstruction-Induced Renal Injury, Inflammation, and Fibrosis: A Comprehensive Approach to Reducing Oxidative Stress, Apoptosis, and Ferroptosis. Antioxidants (Basel) 2024; 14:13. [PMID: 39857346 PMCID: PMC11762340 DOI: 10.3390/antiox14010013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 12/18/2024] [Accepted: 12/21/2024] [Indexed: 01/27/2025] Open
Abstract
Chronic kidney disease (CKD) progresses through mechanisms involving inflammation, fibrosis, and oxidative stress, leading to the gradual structural and functional deterioration of the kidneys. Tormentic acid (TA), a triterpenoid compound with known anti-inflammatory and antioxidant properties, shows significant potential in counteracting these pathological processes. This study explored the protective role of TA in a unilateral ureteral obstruction (UUO)-induced CKD model. Mice received TA through intraperitoneal injections at a dosage of 5 mg/kg per day for 8 consecutive days, commencing a day before the UUO procedure. The TA treatment significantly improved both structural and functional kidney injury. It suppressed cytokine expression and reduced immune cell infiltration, inhibited the activation of the mitogen-activated protein kinase cascade, and alleviated endoplasmic reticulum stress. Moreover, TA displayed potent anti-fibrotic effects by reversing epithelial-to-mesenchymal transition and inhibiting Smad2/3 activation, reducing extracellular matrix deposition. TA also mitigated oxidative stress by attenuating lipid peroxidation and boosting antioxidant defenses. Additionally, it inhibited apoptosis and ferroptosis by reducing oxidative stress and modulating key cell death markers. Collectively, these findings indicate that TA provides comprehensive renoprotection in the UUO model by effectively targeting inflammation, fibrosis, oxidative stress, and tubular cell death in CKD progression.
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Affiliation(s)
- Ah Young Yang
- Department of Immunology, School of Medicine, Daegu Catholic University, Daegu 42472, Republic of Korea; (A.Y.Y.); (J.-Y.K.); (M.-G.G.)
| | - Jung-Yeon Kim
- Department of Immunology, School of Medicine, Daegu Catholic University, Daegu 42472, Republic of Korea; (A.Y.Y.); (J.-Y.K.); (M.-G.G.)
| | - Mi-Gyeong Gwon
- Department of Immunology, School of Medicine, Daegu Catholic University, Daegu 42472, Republic of Korea; (A.Y.Y.); (J.-Y.K.); (M.-G.G.)
| | - Hyun Hee Kwon
- Department of Internal Medicine, School of Medicine, Daegu Catholic University, Daegu 42472, Republic of Korea;
| | - Jaechan Leem
- Department of Immunology, School of Medicine, Daegu Catholic University, Daegu 42472, Republic of Korea; (A.Y.Y.); (J.-Y.K.); (M.-G.G.)
| | - Eon-Ju Jeon
- Department of Internal Medicine, School of Medicine, Daegu Catholic University, Daegu 42472, Republic of Korea;
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Zhu LR, Cui W, Liu HP. Research progress and advances in endoplasmic reticulum stress regulation of acute kidney injury. Ren Fail 2024; 46:2433160. [PMID: 39586579 PMCID: PMC11590187 DOI: 10.1080/0886022x.2024.2433160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 11/15/2024] [Accepted: 11/18/2024] [Indexed: 11/27/2024] Open
Abstract
Acute kidney injury (AKI) is a common and severe clinical disorder in which endoplasmic reticulum (ER) stress plays an important regulatory role. In this review, we summarize the research progress on the relationship between ER stress and AKI. It emphasizes the importance of maintaining a balance between promoting and protecting ER stress during AKI and highlights the potential of ER stress-targeted drugs as a new therapeutic approach for AKI. The article also discusses the need for developing drugs that target ER stress effectively while avoiding adverse effects on normal cells and tissues. The review concludes that with a more comprehensive understanding of ER stress mechanisms and advancements in research techniques, more effective treatment options for AKI can be developed in the future.
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Affiliation(s)
- Li-Ran Zhu
- Anhui Institute of Pediatric Research, Anhui Provincial Children’s Hospital (Children’s Hospital of Fudan University Anhui Hospital; Children’s Medical Center of Anhui Medical University), Hefei, Anhui, China
| | - Wei Cui
- Department of Scientific Research and Education, Anhui Provincial Children’s Hospital (Children’s Hospital of Fudan University Anhui Hospital; Children’s Medical Center of Anhui Medical University), Hefei, Anhui, China
| | - Hai-Peng Liu
- Anhui Institute of Pediatric Research, Anhui Provincial Children’s Hospital (Children’s Hospital of Fudan University Anhui Hospital; Children’s Medical Center of Anhui Medical University), Hefei, Anhui, China
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Sakhi IB, De Combiens E, Frachon N, Durussel F, Brideau G, Nemazanyy I, Frère P, Thévenod F, Lee WK, Zeng Q, Klein C, Lourdel S, Bignon Y. A novel transgenic mouse model highlights molecular disruptions involved in the pathogenesis of Dent disease 1. Gene 2024; 928:148766. [PMID: 39019097 DOI: 10.1016/j.gene.2024.148766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 07/02/2024] [Accepted: 07/12/2024] [Indexed: 07/19/2024]
Abstract
Dent disease (DD) is a hereditary renal disorder characterized by low molecular weight (LMW) proteinuria and progressive renal failure. Inactivating mutations of the CLCN5 gene encoding the 2Cl-/H+exchanger ClC-5 have been identified in patients with DD type 1. ClC-5 is essentially expressed in proximal tubules (PT) where it is thought to play a role in maintaining an efficient endocytosis of LMW proteins. However, the exact pathological roles of ClC-5 in progressive dysfunctions observed in DD type 1 are still unclear. To address this issue, we designed a mouse model carrying the most representative type of ClC-5 missense mutations found in DD patients. These mice showed a characteristic DD type 1 phenotype accompanied by altered endo-lysosomal system and autophagy functions. With ageing, KI mice showed increased renal fibrosis, apoptosis and major changes in cell metabolic functions as already suggested in previous DD models. Furthermore, we made the interesting new discovery that the Lipocalin-2-24p3R pathway might be involved in the progression of the disease. These results suggest a crosstalk between the proximal and distal nephron in the pathogenesis mechanisms involved in DD with an initial PT impairment followed by the Lipocalin-2 internalisation and 24p3R overexpression in more distal segments of the nephron. This first animal model of DD carrying a pathogenic mutation of Clcn5 and our findings pave the way aimed at exploring therapeutic strategies to limit the consequences of ClC-5 disruption in patients with DD type 1 developing chronic kidney disease.
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Affiliation(s)
- Imene Bouchra Sakhi
- University of Zurich - Institute of Anatomy, Zurich CH-8057, Switzerland; Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Paris F-75006, France; CNRS EMR8228, Paris F-75006, France.
| | - Elise De Combiens
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Paris F-75006, France; CNRS EMR8228, Paris F-75006, France
| | - Nadia Frachon
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Paris F-75006, France; CNRS EMR8228, Paris F-75006, France
| | - Fanny Durussel
- Department of Biomedical Sciences, University of Lausanne, Switzerland
| | - Gaelle Brideau
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Paris F-75006, France; CNRS EMR8228, Paris F-75006, France
| | - Ivan Nemazanyy
- Platform for Metabolic Analyses, Structure Fédérative de Recherche Necker, INSERM US24/CNRS UAR 3633, Paris, France
| | - Perrine Frère
- Sorbonne Université, INSERM, Unité mixte de Recherche 1155, Kidney Research Centre, AP-HP, Hôpital Tenon, Paris, France
| | - Frank Thévenod
- Institute for Physiology, Pathophysiology and Toxicology, Center for Biomedical Education and Research, Witten/Herdecke University, Witten, Germany; Physiology and Pathophysiology of Cells and Membranes, Medical School OWL, Bielefeld University, Bielefeld, Germany
| | - Wing-Kee Lee
- Physiology and Pathophysiology of Cells and Membranes, Medical School OWL, Bielefeld University, Bielefeld, Germany
| | - Qinghe Zeng
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Paris F-75006, France; Laboratoire d'Informatique Paris Descartes (LIPADE), Université Paris Cité, Paris, France
| | - Christophe Klein
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Paris F-75006, France
| | - Stéphane Lourdel
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Paris F-75006, France; CNRS EMR8228, Paris F-75006, France
| | - Yohan Bignon
- Department of Biomedical Sciences, University of Lausanne, Switzerland.
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Mirzavi F, Rajabian A, Hosseini H. The potential protective role of carotenoids from saffron: A focus on endoplasmic reticulum stress-related organ damage. Food Sci Nutr 2024; 12:6108-6122. [PMID: 39554322 PMCID: PMC11561782 DOI: 10.1002/fsn3.4289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 05/16/2024] [Accepted: 06/08/2024] [Indexed: 11/19/2024] Open
Abstract
The anticancer, antioxidant, and immunomodulatory properties of carotenoids from saffron or apocarotenoids (e.g., crocin, safranal, crocetin, and picrocrocin) have prompted research into their benefits. Apocarotenoids seem to be effective compound for the treatment of chronic diseases, such as neurodegenerative, cardiovascular, cancer, respiratory, and metabolic disorders. Endoplasmic reticulum (ER) is an essential organelle found in the cytoplasm of eukaryotic cells that participates in the biosynthesis of proteins, lipids, and steroid hormones. Given the role of the ER in the regulation of several fundamental biological processes, including metabolic pathways and immune responses, aberrant ER function can have a significant influence on these vital processes and result in serious pathological consequences. Exposure of cell to adverse environmental challenges, such as toxic agents, ischemia, and so on, causes accumulation of unfolded or misfolded proteins in the ER lumen, also called ER stress. There is a growing evidence to suggest that ER disturbance in the form of oxidative/nitrosative stress and subsequent apoptotic cell death plays major roles in the pathogenesis of many human diseases, including cardiovascular diseases, diabetes mellitus, neurodegenerative diseases, and liver diseases. Apocarotenoids with their unique properties can modulate ER stress through PERK/eIF2α/ATF4/CHOP (protein kinase R (PKR)-like ER kinase/eukaryotic initiation factor 2α/activating transcription factor 4/C/EBP /homologous protein) and X-Box Binding Protein 1/activating transcription factor 6 (XBP1/ATF6) pathways. In addition, they suppress apoptosis through inhibition of endoplasmic and mitochondrial-dependent caspase cascade and can stimulate SIRT1 (silent information regulator 1) and Nrf2 (nuclear factor erythroid 2-related factor 2) expression, thereby leading to protection against oxidative stress. This review summarizes the potential benefits of apocarotenoids in various ER-stress-related disorders.
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Affiliation(s)
- Farshad Mirzavi
- Cardiovascular Diseases Research CenterBirjand University of Medical SciencesBirjandIran
| | - Arezoo Rajabian
- Neuroscience Research CenterMashhad University of Medical SciencesMashhadIran
- Department of NeuroscienceFaculty of Medicine, Mashhad University of Medical SciencesMashhadIran
| | - Hossein Hosseini
- Department of Clinical BiochemistryFaculty of Medicine, Mashhad University of Medical SciencesMashhadIran
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9
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Duara J, Torres M, Gurumani M, Molina David J, Njeim R, Kim JJ, Mitrofanova A, Ge M, Sloan A, Müller-Deile J, Schiffer M, Merscher S, Fornoni A. Oxysterol-binding protein-like 7 deficiency leads to ER stress-mediated apoptosis in podocytes and proteinuria. Am J Physiol Renal Physiol 2024; 327:F340-F350. [PMID: 38961844 PMCID: PMC11460532 DOI: 10.1152/ajprenal.00319.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 06/21/2024] [Accepted: 06/21/2024] [Indexed: 07/05/2024] Open
Abstract
Chronic kidney disease (CKD) is associated with renal lipid dysmetabolism among a variety of other pathways. We recently demonstrated that oxysterol-binding protein-like 7 (OSBPL7) modulates the expression and function of ATP-binding cassette subfamily A member 1 (ABCA1) in podocytes, a specialized type of cell essential for kidney filtration. Drugs that target OSBPL7 lead to improved renal outcomes in several experimental models of CKD. However, the role of OSBPL7 in podocyte injury remains unclear. Using mouse models and cellular assays, we investigated the influence of OSBPL7 deficiency on podocytes. We demonstrated that reduced renal OSBPL7 levels as observed in two different models of experimental CKD are linked to increased podocyte apoptosis, primarily mediated by heightened endoplasmic reticulum (ER) stress. Although as expected, the absence of OSBPL7 also resulted in lipid dysregulation (increased lipid droplets and triglycerides content), OSBPL7 deficiency-related lipid dysmetabolism did not contribute to podocyte injury. Similarly, we demonstrated that the decreased autophagic flux we observed in OSBPL7-deficient podocytes was not the mechanistic link between OSBPL7 deficiency and apoptosis. In a complementary zebrafish model, osbpl7 knockdown was sufficient to induce proteinuria and morphological damage to the glomerulus, underscoring its physiological relevance. Our study sheds new light on the mechanistic link between OSBPL7 deficiency and podocyte injury in glomerular diseases associated with CKD, and it strengthens the role of OSBPL7 as a novel therapeutic target.NEW & NOTEWORTHY OSBPL7 and ER stress comprise a central mechanism in glomerular injury. This study highlights a crucial link between OSBPL7 deficiency and ER stress in CKD. OSBPL7 deficiency causes ER stress, leading to podocyte apoptosis. There is a selective effect on lipid homeostasis in that OSBPL7 deficiency affects lipid homeostasis, altering cellular triglyceride but not cholesterol content. The interaction of ER stress and apoptosis supports that ER stress, not reduced autophagy, is the main driver of apoptosis in OSBPL7-deficient podocytes.
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Affiliation(s)
- Joanne Duara
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida, United States
- Department of Pediatrics/Division of Neonatology, Batchelor Children's Research Institute, Holtz Children's Hospital, University of Miami Miller School of Medicine, Miami, Florida, United States
| | - Maria Torres
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida, United States
- Boston University, Boston, Massachusetts, United States
| | - Margaret Gurumani
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida, United States
- Boston University, Boston, Massachusetts, United States
| | - Judith Molina David
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida, United States
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, United States
| | - Rachel Njeim
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida, United States
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, United States
| | - Jin-Ju Kim
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida, United States
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, United States
| | - Alla Mitrofanova
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida, United States
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, United States
| | - Mengyuan Ge
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida, United States
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, United States
| | - Alexis Sloan
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida, United States
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, United States
| | - Janina Müller-Deile
- Department of Nephrology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Mario Schiffer
- Department of Nephrology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Mount Desert Island Biological Laboratories, Salisbury Cove, Maine, United States
| | - Sandra Merscher
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida, United States
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, United States
| | - Alessia Fornoni
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida, United States
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, United States
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10
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Elseweidy MM, Asker ME, El-Zeiky RR, Elmaghraby AM, Elrashidy RA. Sitagliptin alleviates renal steatosis and endoplasmic reticulum stress in high fat diet-induced obese rats by targeting SREBP-1/CD36 signaling pathway. Eur J Pharmacol 2024; 977:176745. [PMID: 38880220 DOI: 10.1016/j.ejphar.2024.176745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 06/08/2024] [Accepted: 06/13/2024] [Indexed: 06/18/2024]
Abstract
High fat diet (HFD) consumption can cause dysregulation of glucose and lipid metabolism, coupled with increased ectopic lipid deposition in renal tissue leading to steatosis and dysfunction. Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor clinically used for type II diabetes therapy; however its effect on renal steatosis in obese state is still uncertain. Herein, obesity was induced by feeding male Wistar rats HFD for 18 weeks, thereafter received either drug vehicle, or sitagliptin (10 mg/kg, PO) along with HFD for further 6 weeks and compared with age-matched rats receiving normal chow diet (NCD). After 24 weeks, serum and kidneys were collected for histological and biochemical assessments. Compared to NCD-fed group, HFD-fed rats displayed marked weight gain, increased fat mass, insulin resistance, dyslipidemia, impaired kidney functions and renal histological alterations. Sitagliptin effectively ameliorated obesity and related metabolic perturbations and improved kidney architecture and function. There were increased levels of triglycerides and cluster of differentiation 36 (CD36) in kidneys of obese rats, that were lowered by sitagliptin therapy. Sitagliptin significantly repressed the expression of lipogenesis genes, while up-regulated genes involved in mitochondrial biogenesis and fatty acid oxidation in kidneys of HFD-fed rats. Sitagliptin was found to induce down-regulation of endoplasmic reticulum (ER) stress and apoptotic markers in kidneys of obese rats. These findings together may emphasize a novel concept that sitagliptin can be an effective therapeutic approach for halting obesity-related renal steatosis and CKD.
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Affiliation(s)
- Mohammed M Elseweidy
- Biochemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt.
| | - Mervat E Asker
- Biochemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt
| | - Reham R El-Zeiky
- Biochemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt
| | - Asmaa M Elmaghraby
- Histology and Cell Biology Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
| | - Rania A Elrashidy
- Biochemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt.
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11
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Mu W, Zhi Y, Zhou J, Wang C, Chai K, Fan Z, Lv G. Endoplasmic reticulum stress and quality control in relation to cisplatin resistance in tumor cells. Front Pharmacol 2024; 15:1419468. [PMID: 38948460 PMCID: PMC11211601 DOI: 10.3389/fphar.2024.1419468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Accepted: 05/29/2024] [Indexed: 07/02/2024] Open
Abstract
The endoplasmic reticulum (ER) is a crucial organelle that orchestrates key cellular functions like protein folding and lipid biosynthesis. However, it is highly sensitive to disturbances that lead to ER stress. In response, the unfolded protein response (UPR) activates to restore ER homeostasis, primarily through three sensors: IRE1, ATF6, and PERK. ERAD and autophagy are crucial in mitigating ER stress, yet their dysregulation can lead to the accumulation of misfolded proteins. Cisplatin, a commonly used chemotherapy drug, induces ER stress in tumor cells, activating complex signaling pathways. Resistance to cisplatin stems from reduced drug accumulation, activation of DNA repair, and anti-apoptotic mechanisms. Notably, cisplatin-induced ER stress can dualistically affect tumor cells, promoting either survival or apoptosis, depending on the context. ERAD is crucial for degrading misfolded proteins, whereas autophagy can protect cells from apoptosis or enhance ER stress-induced apoptosis. The complex interaction between ER stress, cisplatin resistance, ERAD, and autophagy opens new avenues for cancer treatment. Understanding these processes could lead to innovative strategies that overcome chemoresistance, potentially improving outcomes of cisplatin-based cancer treatments. This comprehensive review provides a multifaceted perspective on the complex mechanisms of ER stress, cisplatin resistance, and their implications in cancer therapy.
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Affiliation(s)
| | | | | | | | | | - Zhongqi Fan
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Guoyue Lv
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China
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12
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Wang Y, Sun N, He R, Wang Z, Jin J, Gao T, Qu J. Molecular characterization of m6A RNA methylation regulators with features of immune dysregulation in IgA nephropathy. Clin Exp Med 2024; 24:92. [PMID: 38693353 PMCID: PMC11062981 DOI: 10.1007/s10238-024-01346-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Accepted: 04/02/2024] [Indexed: 05/03/2024]
Abstract
The role of RNA N6-methyladenosine (m6A) modification in immunity is being elucidated. This study aimed to explore the potential association between m6A regulators and the immune microenvironment in IgA nephropathy (IgAN). The expression profiles of 24 m6A regulators in 107 IgAN patients were obtained from the Gene Expression Omnibus (GEO) database. The least absolute shrinkage and selection operator (LASSO) regression and logistic regression analysis were utilized to construct a model for distinguishing IgAN from control samples. Based on the expression levels of m6A regulators, unsupervised clustering was used to identify m6A-induced molecular clusters in IgAN. Gene set enrichment analysis (GSEA) and immunocyte infiltration among different clusters were examined. The gene modules with the highest correlation for each of the three clusters were identified by weighted gene co-expression network analysis (WGCNA). A model containing 10 m6A regulators was developed using LASSO and logistic regression analyses. Three molecular clusters were determined using consensus clustering of 24 m6A regulators. A decrease in the expression level of YTHDF2 in IgAN samples was significantly negatively correlated with an increase in resting natural killer (NK) cell infiltration and was positively correlated with the abundance of M2 macrophage infiltration. The risk scores calculated by the nomogram were significantly higher for cluster-3, and the expression levels of m6A regulators in this cluster were generally low. Immunocyte infiltration and pathway enrichment results for cluster-3 differed significantly from those for the other two clusters. Finally, the expression of YTHDF2 was significantly decreased in IgAN based on immunohistochemical staining. This study demonstrated that m6A methylation regulators play a significant role in the regulation of the immune microenvironment in IgAN. Based on m6A regulator expression patterns, IgAN can be classified into multiple subtypes, which might provide additional insights into novel therapeutic methods for IgAN.
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Affiliation(s)
- Yihao Wang
- Department of Nephrology, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, 200003, China
| | - Nan Sun
- Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Rui He
- Shanghai Immune Therapy Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Zida Wang
- Department of Emergency, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Jingsi Jin
- Shanghai Immune Therapy Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Ting Gao
- Department of Emergency, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
| | - Junwen Qu
- Department of Urology, Jiading Branch, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201899, China.
- Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
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13
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Saaoud F, Lu Y, Xu K, Shao Y, Praticò D, Vazquez-Padron RI, Wang H, Yang X. Protein-rich foods, sea foods, and gut microbiota amplify immune responses in chronic diseases and cancers - Targeting PERK as a novel therapeutic strategy for chronic inflammatory diseases, neurodegenerative disorders, and cancer. Pharmacol Ther 2024; 255:108604. [PMID: 38360205 PMCID: PMC10917129 DOI: 10.1016/j.pharmthera.2024.108604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 01/05/2024] [Accepted: 01/29/2024] [Indexed: 02/17/2024]
Abstract
The endoplasmic reticulum (ER) is a cellular organelle that is physiologically responsible for protein folding, calcium homeostasis, and lipid biosynthesis. Pathological stimuli such as oxidative stress, ischemia, disruptions in calcium homeostasis, and increased production of normal and/or folding-defective proteins all contribute to the accumulation of misfolded proteins in the ER, causing ER stress. The adaptive response to ER stress is the activation of unfolded protein response (UPR), which affect a wide variety of cellular functions to maintain ER homeostasis or lead to apoptosis. Three different ER transmembrane sensors, including PKR-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme-1 (IRE1), are responsible for initiating UPR. The UPR involves a variety of signal transduction pathways that reduce unfolded protein accumulation by boosting ER-resident chaperones, limiting protein translation, and accelerating unfolded protein degradation. ER is now acknowledged as a critical organelle in sensing dangers and determining cell life and death. On the other hand, UPR plays a critical role in the development and progression of several diseases such as cardiovascular diseases (CVD), metabolic disorders, chronic kidney diseases, neurological disorders, and cancer. Here, we critically analyze the most current knowledge of the master regulatory roles of ER stress particularly the PERK pathway as a conditional danger receptor, an organelle crosstalk regulator, and a regulator of protein translation. We highlighted that PERK is not only ER stress regulator by sensing UPR and ER stress but also a frontier sensor and direct senses for gut microbiota-generated metabolites. Our work also further highlighted the function of PERK as a central hub that leads to metabolic reprogramming and epigenetic modification which further enhanced inflammatory response and promoted trained immunity. Moreover, we highlighted the contribution of ER stress and PERK in the pathogenesis of several diseases such as cancer, CVD, kidney diseases, and neurodegenerative disorders. Finally, we discuss the therapeutic target of ER stress and PERK for cancer treatment and the potential novel therapeutic targets for CVD, metabolic disorders, and neurodegenerative disorders. Inhibition of ER stress, by the development of small molecules that target the PERK and UPR, represents a promising therapeutic strategy.
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Affiliation(s)
- Fatma Saaoud
- Lemole Center for Integrated Lymphatics and Vascular Research, Department of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA
| | - Yifan Lu
- Lemole Center for Integrated Lymphatics and Vascular Research, Department of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA
| | - Keman Xu
- Lemole Center for Integrated Lymphatics and Vascular Research, Department of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA
| | - Ying Shao
- Lemole Center for Integrated Lymphatics and Vascular Research, Department of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA
| | - Domenico Praticò
- Alzheimer's Center, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA
| | | | - Hong Wang
- Metabolic Disease Research, Department of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA
| | - Xiaofeng Yang
- Lemole Center for Integrated Lymphatics and Vascular Research, Department of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA; Metabolic Disease Research, Department of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA.
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14
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Wang C, Chen H, Su H, Sheng Q, Lang Y, Yu Q, Lv Z, Wang R. The role and mechanism of RIPK1 in vascular endothelial dysfunction in chronic kidney disease. FASEB J 2024; 38:e23446. [PMID: 38275125 DOI: 10.1096/fj.202301916rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 12/28/2023] [Accepted: 01/10/2024] [Indexed: 01/27/2024]
Abstract
Endothelial dysfunction is common in patients with chronic kidney disease (CKD) and cardiovascular events, but the mechanism is unclear. In our study, we found elevated levels of RIPK1 in patients with CKD and cardiovascular events through bioinformation analysis. Elevated RIPK1 levels were found in serum samples of CKD patients and were associated with vascular endothelial dysfunction and renal function. We constructed the five of six nephrectomy of CKD mice model, finding that RIPK1 expressions were elevated in abdominal aorta endothelial cells. After RIPK1 inhibition and overexpression, it was found that RIPK1 could regulate the expression of endothelial nitric oxide synthase (eNOS) and cell adhesion molecule 1 (ICAM-1), and activation of inflammatory responses and endoplasmic reticulum (ER) stress. In addition, uremic toxin induced abnormal expression of RIPK1 in vitro. We observed RIPK1-mediating endothelial dysfunction and inflammation responses by ER stress pathways through gain and loss of function. In order to explore the specific mechanism, we conducted co-immunoprecipitation and expression regulation of RIPK1 and IKK, finding that RIPK1 formed complex with IKK and regulated IKK expression. In conclusion, we demonstrated that RIPK1 levels were closely associated with vascular endothelial dysfunction in patients with CKD. With uremic toxins, RIPK1 expression was elevated, which led to the activation of inflammation through the ER stress pathway, resulting in vascular endothelial injury. Besides, activation of RIPK1-IKK-NF-κB axis was a key driver of endothelial dysfunction in CKD. Our study provides a new perspective for the study of cardiovascular events in CKD.
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Affiliation(s)
- Cheng Wang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Huimin Chen
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Hong Su
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Department of Nephrology, Shandong Provincial Hospital, Shandong University, Jinan, China
| | - Qinghao Sheng
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Yating Lang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Qun Yu
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Zhimei Lv
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Department of Nephrology, Shandong Provincial Hospital, Shandong University, Jinan, China
| | - Rong Wang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Department of Nephrology, Shandong Provincial Hospital, Shandong University, Jinan, China
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15
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Zhang J, Zhao Y, Gong N. XBP1 Modulates the Aging Cardiorenal System by Regulating Oxidative Stress. Antioxidants (Basel) 2023; 12:1933. [PMID: 38001786 PMCID: PMC10669121 DOI: 10.3390/antiox12111933] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 10/25/2023] [Accepted: 10/27/2023] [Indexed: 11/26/2023] Open
Abstract
X-box binding protein 1 (XBP1) is a unique basic-region leucine zipper (bZIP) transcription factor. Over recent years, the powerful biological functions of XBP1 in oxidative stress have been gradually revealed. When the redox balance remains undisturbed, oxidative stress plays a role in physiological adaptations and signal transduction. However, during the aging process, increased cellular senescence and reduced levels of endogenous antioxidants cause an oxidative imbalance in the cardiorenal system. Recent studies from our laboratory and others have indicated that these age-related cardiorenal diseases caused by oxidative stress are guided and controlled by a versatile network composed of diversified XBP1 pathways. In this review, we describe the mechanisms that link XBP1 and oxidative stress in a range of cardiorenal disorders, including mitochondrial instability, inflammation, and alterations in neurohumoral drive. Furthermore, we propose that differing degrees of XBP1 activation may cause beneficial or harmful effects in the cardiorenal system. Gaining a comprehensive understanding of how XBP1 exerts influence on the aging cardiorenal system by regulating oxidative stress will enhance our ability to provide new directions and strategies for cardiovascular and renal safety outcomes.
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Affiliation(s)
- Ji Zhang
- Anhui Province Key Laboratory of Genitourinary Diseases, Department of Urology, The First Affiliated Hospital of Anhui Medical University, Institute of Urology, Anhui Medical University, Hefei 230022, China;
- Key Laboratory of Organ Transplantation of Ministry of Education, Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, National Health Commission and Chinese Academy of Medical Sciences, Huazhong University of Science and Technology, Wuhan 430030, China;
| | - Yuanyuan Zhao
- Key Laboratory of Organ Transplantation of Ministry of Education, Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, National Health Commission and Chinese Academy of Medical Sciences, Huazhong University of Science and Technology, Wuhan 430030, China;
| | - Nianqiao Gong
- Key Laboratory of Organ Transplantation of Ministry of Education, Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, National Health Commission and Chinese Academy of Medical Sciences, Huazhong University of Science and Technology, Wuhan 430030, China;
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16
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Su BL, Wang LL, Zhang LY, Zhang S, Li Q, Chen GY. Potential role of microRNA-503 in Icariin-mediated prevention of high glucose-induced endoplasmic reticulum stress. World J Diabetes 2023; 14:1234-1248. [PMID: 37664468 PMCID: PMC10473951 DOI: 10.4239/wjd.v14.i8.1234] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 06/12/2023] [Accepted: 07/07/2023] [Indexed: 08/11/2023] Open
Abstract
BACKGROUND Dysregulated microRNA (miRNA) is crucial in the progression of diabetic nephropathy (DN). AIM To investigate the potential molecular mechanism of Icariin (ICA) in regulating endoplasmic reticulum (ER) stress-mediated apoptosis in high glucose (HG)-induced primary rat kidney cells (PRKs), with emphasis on the role of miR-503 and sirtuin 4 (SIRT4) in this process. METHODS Single intraperitoneal injection of streptozotocin (65 mg/kg) in Sprague-Dawley rats induce DN in the in vivo hyperglycemic model. Glucose-treated PRKs were used as an in vitro HG model. An immunofluorescence assay identified isolated PRKs. Cell Counting Kit-8 and flow cytometry analyzed the effect of ICA treatment on cell viability and apoptosis, respectively. Real-time quantitative polymerase chain reaction and western blot analyzed the levels of ER stress-related proteins. Dual luciferase analysis of miR-503 binding to downstream SIRT4 was performed. RESULTS ICA treatment alleviated the upregulated miR-503 expression in vivo (DN) and in vitro (HG). Mechanistically, ICA reduced HG-induced miR-503 overexpression, thereby counteracting its function in downregulating SIRT4 levels. ICA regulated the miR-503/SIRT4 axis and subsequent ER stress to alleviate HG-induced PRKs injury. CONCLUSION ICA reduced HG-mediated inhibition of cell viability, promotion of apoptosis, and ER stress in PRKs. These effects involved regulation of the miR-503/SIRT4 axis. These findings indicate the potential of ICA to treat DN, and implicate miR-503 as a viable target for therapeutic interventions in DN.
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Affiliation(s)
- Bao-Lin Su
- Department of Nephrology, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou 510405, Guangdong Province, China
| | - Liang-Liang Wang
- Department of Nephrology, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou 510405, Guangdong Province, China
| | - Liang-You Zhang
- Department of Nephrology, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou 510405, Guangdong Province, China
| | - Shu Zhang
- Department of Nephrology, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou 510405, Guangdong Province, China
| | - Qiang Li
- Department of Nephrology, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou 510405, Guangdong Province, China
| | - Gang-Yi Chen
- Department of Nephrology, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou 510405, Guangdong Province, China
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17
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Wu D, Huang LF, Chen XC, Huang XR, Li HY, An N, Tang JX, Liu HF, Yang C. Research progress on endoplasmic reticulum homeostasis in kidney diseases. Cell Death Dis 2023; 14:473. [PMID: 37500613 PMCID: PMC10374544 DOI: 10.1038/s41419-023-05905-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 06/10/2023] [Accepted: 06/19/2023] [Indexed: 07/29/2023]
Abstract
The endoplasmic reticulum (ER) plays important roles in biosynthetic and metabolic processes, including protein and lipid synthesis, Ca2+ homeostasis regulation, and subcellular organelle crosstalk. Dysregulation of ER homeostasis can cause toxic protein accumulation, lipid accumulation, and Ca2+ homeostasis disturbance, leading to cell injury and even death. Accumulating evidence indicates that the dysregulation of ER homeostasis promotes the onset and progression of kidney diseases. However, maintaining ER homeostasis through unfolded protein response, ER-associated protein degradation, autophagy or ER-phagy, and crosstalk with other organelles may be potential therapeutic strategies for kidney disorders. In this review, we summarize the recent research progress on the relationship and molecular mechanisms of ER dysfunction in kidney pathologies. In addition, the endogenous protective strategies for ER homeostasis and their potential application for kidney diseases have been discussed.
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Affiliation(s)
- Dan Wu
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, 524001, Zhanjiang, Guangdong, China
| | - Li-Feng Huang
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, 524001, Zhanjiang, Guangdong, China
| | - Xiao-Cui Chen
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, 524001, Zhanjiang, Guangdong, China
| | - Xiao-Rong Huang
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, 524001, Zhanjiang, Guangdong, China
| | - Hui-Yuan Li
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, 524001, Zhanjiang, Guangdong, China
| | - Ning An
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, 524001, Zhanjiang, Guangdong, China
| | - Ji-Xin Tang
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, 524001, Zhanjiang, Guangdong, China
| | - Hua-Feng Liu
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, 524001, Zhanjiang, Guangdong, China.
| | - Chen Yang
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, 524001, Zhanjiang, Guangdong, China.
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18
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Li X, Bai Y, Bi Y, Wu Q, Xu S. Baicalin suppressed necroptosis and inflammation against chlorpyrifos toxicity; involving in ER stress and oxidative stress in carp gills. FISH & SHELLFISH IMMUNOLOGY 2023:108883. [PMID: 37285874 DOI: 10.1016/j.fsi.2023.108883] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Revised: 06/03/2023] [Accepted: 06/05/2023] [Indexed: 06/09/2023]
Abstract
Chlorpyrifos (CPF) has caused large-scale pollution worldwide and posed a threat to non-target organisms. Baicalein (BAI) is a flavonoid extract with anti-oxidant and anti-inflammatory activities. The gills are the mucosal immune organ and the first physical barrier of fish. However, it is not clear whether BAI counteracts organophosphorus pesticide CPF exposure-caused gill damage. Therefore, we established the CPF exposure and BAI intervention models by adding 23.2 μg/L CPF in water and/or 0.15 g/kg BAI in feed for 30 days. The results showed that CPF exposure could cause gill histopathology lesions. Moreover, CPF exposure led to endoplasmic reticulum (ER) stress, caused oxidative stress and Nrf2 pathway activation, and triggered NF-κB-mediated inflammation reaction and necroptosis in carp gills. BAI adding effectively relieved the pathological changes, and lighten inflammation and necroptosis involving in the elF2α/ATF4 and ATF6 pathways through binding to GRP78 protein. Moreover, BAI could ease oxidative stress, but did not affect Nrf2 pathway in carp gills under CPF exposure. These results suggested that BAI feeding could alleviate necroptosis and inflammation against chlorpyrifos toxicity through elF2α/ATF4 and ATF6 axis. The results partially explained the poisoning effect of CPF, and showed BAI could be act as an antidote for organophosphorus pesticides.
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Affiliation(s)
- Xiaojing Li
- College of Animal Science and Technology, Northeast Agricultural University, Harbin, 150030, PR China
| | - Yichen Bai
- College of Animal Science and Technology, Northeast Agricultural University, Harbin, 150030, PR China
| | - Yanju Bi
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China
| | - Qian Wu
- College of Animal Science and Technology, Northeast Agricultural University, Harbin, 150030, PR China
| | - Shiwen Xu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China.
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Cheng AS, Li X. The Potential Biotherapeutic Targets of Contrast-Induced Acute Kidney Injury. Int J Mol Sci 2023; 24:8254. [PMID: 37175958 PMCID: PMC10178966 DOI: 10.3390/ijms24098254] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Revised: 04/27/2023] [Accepted: 04/28/2023] [Indexed: 05/15/2023] Open
Abstract
Contrast-induced acute kidney injury (CI-AKI) is manifested by an abrupt decline in kidney function as a consequence of intravascular exposure to contrast media. With the increased applicability of medical imaging and interventional procedures that utilize contrast media for clinical diagnosis, CI-AKI is becoming the leading cause of renal dysfunction. The pathophysiological mechanism associated with CI-AKI involves renal medullary hypoxia, the direct toxicity of contrast agents, oxidative stress, apoptosis, inflammation, and epigenetic regulation. To date, there is no effective therapy for CI-AKI, except for the development of strategies that could reduce the toxicity profiles of contrast media. While most of these strategies have failed, evidence has shown that the proper use of personalized hydration, contrast medium, and high-dose statins may reduce the occurrence of CI-AKI. However, adequate risk predication and attempts to develop preventive strategies can be considered as the key determinants that can help eliminate CI-AKI. Additionally, a deeper understanding of the pathophysiological mechanism of CI-AKI is crucial to uncover molecular targets for the prevention of CI-AKI. This review has taken a step further to solidify the current known molecular mechanisms of CI-AKI and elaborate the biomarkers that are used to detect early-stage CI-AKI. On this foundation, this review will analyze the molecular targets relating to apoptosis, inflammation, oxidative stress, and epigenetics, and, thus, provide a strong rationale for therapeutic intervention in the prevention of CI-AKI.
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Affiliation(s)
- Alice Shasha Cheng
- Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA;
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
| | - Xiaogang Li
- Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA;
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
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20
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Chen Z, Zhang SL. Endoplasmic Reticulum Stress: A Key Regulator of Cardiovascular Disease. DNA Cell Biol 2023. [PMID: 37140435 DOI: 10.1089/dna.2022.0532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/05/2023] Open
Abstract
The problems associated with economic development and social progress have led to an increase in the occurrence of cardiovascular diseases (CVDs), which affect the health of an increasing number of people and are a leading cause of disease and population mortality worldwide. Endoplasmic reticulum stress (ERS), a hot topic of interest for scholars in recent years, has been confirmed in numerous studies to be an important pathogenetic basis for many metabolic diseases and play an important role in maintaining physiological processes. The endoplasmic reticulum (ER) is a major organelle that is involved in protein folding and modification synthesis, and ERS occurs when several physiological and pathological factors allow excessive amounts of unfolded/misfolded proteins to accumulate. ERS often leads to initiation of the unfolded protein response (UPR) in a bid to re-establish tissue homeostasis; however, UPR has been documented to induce vascular remodeling and cardiomyocyte damage under various pathological conditions, leading to or accelerating the development of CVDs such as hypertension, atherosclerosis, and heart failure. In this review, we summarize the latest knowledge gained concerning ERS in terms of cardiovascular system pathophysiology, and discuss the feasibility of targeting ERS as a novel therapeutic target for the treatment of CVDs. Investigation of ERS has immense potential as a new direction for future research involving lifestyle intervention, the use of existing drugs, and the development of novel drugs that target and inhibit ERS.
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Affiliation(s)
- Zhao Chen
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Shi-Liang Zhang
- Section 4, Department of Cardiology, The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
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21
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Delgadillo-Puga C, Sánchez-Castillo DR, Cariño-Cervantes YY, Torre-Villalvazo I, Tovar-Palacio C, Vásquez-Reyes S, Furuzawa-Carballeda J, Acevedo-Carabantes JA, Camacho-Corona MDR, Guzmán-Mar JL, Cisneros-Zevallos L, Tovar AR, Rebollar-Vega R, Hernández-Montes G, Ulloa-Aguirre A, Palacios-Gonzalez B, Noriega LG. Vachellia farnesiana Pods or a Polyphenolic Extract Derived from Them Exert Immunomodulatory, Metabolic, Renoprotective, and Prebiotic Effects in Mice Fed a High-Fat Diet. Int J Mol Sci 2023; 24:ijms24097984. [PMID: 37175691 PMCID: PMC10178983 DOI: 10.3390/ijms24097984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 04/09/2023] [Accepted: 04/21/2023] [Indexed: 05/15/2023] Open
Abstract
Obesity causes systemic inflammation, hepatic and renal damage, as well as gut microbiota dysbiosis. Alternative vegetable sources rich in polyphenols are known to prevent or delay the progression of metabolic abnormalities during obesity. Vachellia farnesiana (VF) is a potent source of polyphenols with antioxidant and anti-inflammatory activities with potential anti-obesity effects. We performed an in vivo preventive or an interventional experimental study in mice and in vitro experiments with different cell types. In the preventive study, male C57BL/6 mice were fed with a Control diet, a high-fat diet, or a high-fat diet containing either 0.1% methyl gallate, 10% powdered VFP, or 0.5%, 1%, or 2% of a polyphenolic extract (PE) derived from VFP (Vachellia farnesiana pods) for 14 weeks. In the intervention study, two groups of mice were fed for 14 weeks with a high-fat diet and then one switched to a high-fat diet with 10% powdered VFP for ten additional weeks. In the in vitro studies, we evaluated the effect of a VFPE (Vachellia farnesiana polyphenolic extract) on glucose-stimulated insulin secretion in INS-1E cells or of naringenin or methyl gallate on mitochondrial activity in primary hepatocytes and C2C12 myotubes. VFP or a VFPE increased whole-body energy expenditure and mitochondrial activity in skeletal muscle; prevented insulin resistance, hepatic steatosis, and kidney damage; exerted immunomodulatory effects; and reshaped fecal gut microbiota composition in mice fed a high-fat diet. VFPE decreased insulin secretion in INS-1E cells, and its isolated compounds naringenin and methyl gallate increased mitochondrial activity in primary hepatocytes and C2C12 myotubes. In conclusion VFP or a VFPE prevented systemic inflammation, insulin resistance, and hepatic and renal damage in mice fed a high-fat diet associated with increased energy expenditure, improved mitochondrial function, and reduction in insulin secretion.
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Affiliation(s)
- Claudia Delgadillo-Puga
- Departamento de Nutrición Animal Dr. Fernando Pérez-Gil Romo, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), Mexico City 14080, Mexico
| | | | - Yonatan Y Cariño-Cervantes
- Departamento de Nutrición Animal Dr. Fernando Pérez-Gil Romo, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), Mexico City 14080, Mexico
| | - Ivan Torre-Villalvazo
- Departamento de Fisiología de la Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), Mexico City 14080, Mexico
| | - Claudia Tovar-Palacio
- Dirección de Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), Mexico City 14080, Mexico
| | - Sarai Vásquez-Reyes
- Departamento de Fisiología de la Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), Mexico City 14080, Mexico
| | - Janette Furuzawa-Carballeda
- Departamento de Cirugía Experimental, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), Mexico City 14080, Mexico
| | - Joshua Ayork Acevedo-Carabantes
- Departamento de Fisiología de la Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), Mexico City 14080, Mexico
| | - María Del Rayo Camacho-Corona
- Facultad de Ciencias Químicas, Universidad Autónoma de Nuevo León (UANL), Av. Universidad s/n, Ciudad Universitaria, San Nicolás de Los Garza 66455, Mexico
| | - Jorge Luis Guzmán-Mar
- Facultad de Ciencias Químicas, Universidad Autónoma de Nuevo León (UANL), Av. Universidad s/n, Ciudad Universitaria, San Nicolás de Los Garza 66455, Mexico
| | - Luis Cisneros-Zevallos
- Department of Horticultural Sciences, Texas A&M University, College Station, TX 77843, USA
| | - Armando R Tovar
- Departamento de Fisiología de la Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), Mexico City 14080, Mexico
| | - Rosa Rebollar-Vega
- Red de Apoyo a la Investigación, Universidad Nacional de Autónoma de México, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
| | - Georgina Hernández-Montes
- Red de Apoyo a la Investigación, Universidad Nacional de Autónoma de México, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
| | - Alfredo Ulloa-Aguirre
- Red de Apoyo a la Investigación, Universidad Nacional de Autónoma de México, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
| | - Berenice Palacios-Gonzalez
- Unidad de Vinculación Científica Facultad de Medicina, Instituto Nacional de Medicina Genómica 14, (INMEGEN), Mexico City 16080, Mexico
| | - Lilia G Noriega
- Dirección de Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), Mexico City 14080, Mexico
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The UDPase ENTPD5 regulates ER stress-associated renal injury by mediating protein N-glycosylation. Cell Death Dis 2023; 14:166. [PMID: 36849424 PMCID: PMC9971188 DOI: 10.1038/s41419-023-05685-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Revised: 02/11/2023] [Accepted: 02/14/2023] [Indexed: 03/01/2023]
Abstract
Impaired protein N-glycosylation leads to the endoplasmic reticulum (ER) stress, which triggers adaptive survival or maladaptive apoptosis in renal tubules in diabetic kidney disease (DKD). Therapeutic strategies targeting ER stress are promising for the treatment of DKD. Here, we report a previously unappreciated role played by ENTPD5 in alleviating renal injury by mediating ER stress. We found that ENTPD5 was highly expressed in normal renal tubules; however, ENTPD5 was dynamically expressed in the kidney and closely related to pathological DKD progression in both human patients and mouse models. Overexpression of ENTPD5 relieved ER stress in renal tubular cells, leading to compensatory cell proliferation that resulted in hypertrophy, while ENTPD5 knockdown aggravated ER stress to induce cell apoptosis, leading to renal tubular atrophy and interstitial fibrosis. Mechanistically, ENTPD5-regulated N-glycosylation of proteins in the ER to promote cell proliferation in the early stage of DKD, and continuous hyperglycemia activated the hexosamine biosynthesis pathway (HBP) to increase the level of UDP-GlcNAc, which driving a feedback mechanism that inhibited transcription factor SP1 activity to downregulate ENTPD5 expression in the late stage of DKD. This study was the first to demonstrate that ENTPD5 regulated renal tubule cell numbers through adaptive proliferation or apoptosis in the kidney by modulating the protein N-glycosylation rate in the ER, suggesting that ENTPD5 drives cell fate in response to metabolic stress and is a potential therapeutic target for renal diseases.
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23
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PRE-084 ameliorated kidney injury by reducing endoplasmic reticulum stress in the rat model of adenine-induced chronic kidney disease. Mol Biol Rep 2023; 50:3681-3691. [PMID: 36826683 DOI: 10.1007/s11033-023-08303-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 01/23/2023] [Indexed: 02/25/2023]
Abstract
BACKGROUND Endoplasmic reticulum (ER) stress plays an important role in the development of chronic kidney disease (CKD). Sigma-1 receptors (σ1Rs) are novel chaperone proteins that regulate ER stress. However, effect of σ1R activation on renal ER stress is yet unexplored. So, in the present study we investigated the effects of PRE-084, a σ1R agonist on renal injury and ER stress in the rat model of CKD. METHODS CKD group rats were fed adenine for 28 days and CKD treatment group rats were additionally administered PRE-084 intraperitoneally at 1, 3 and 10 mg/kg body weight dose from Day 22-28. ER stress markers were evaluated using molecular biology techniques such as immunohistochemistry and Western blot. RESULTS Marked kidney injury was observed in CKD rats as revealed by biochemical and histological findings. Expression of ER stress proteins such as phosphorylated protein kinase R-like ER kinase (p-PERK), cleaved activating transcription factor-6 (ATF-6f), phosphorylated inositol requiring enzyme1α (p-IRE1α) and caspase-12 were higher in CKD rats. Nevertheless, CKD rats treated with PRE-084 particularly at 10 mg/kg dose showed considerably lesser kidney injury along with higher expression of σ1R and marked reduction of all the ER stress proteins studied. CONCLUSION Results reveal that PRE-084 likely ameliorated the adenine-induced kidney injury by lowering ER stress through increased σ1R expression.
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24
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What does not kill mesangial cells makes it stronger? The response of the endoplasmic reticulum stress and the O-GlcNAc signaling to ATP depletion. Life Sci 2022; 311:121070. [DOI: 10.1016/j.lfs.2022.121070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 10/06/2022] [Accepted: 10/07/2022] [Indexed: 11/12/2022]
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25
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Protective Effects of Carnosol on Renal Interstitial Fibrosis in a Murine Model of Unilateral Ureteral Obstruction. Antioxidants (Basel) 2022; 11:antiox11122341. [PMID: 36552549 PMCID: PMC9774539 DOI: 10.3390/antiox11122341] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 11/22/2022] [Accepted: 11/23/2022] [Indexed: 11/29/2022] Open
Abstract
Renal fibrosis is a common feature of chronic kidney disease and is a promising therapeutic target. However, there is still limited treatment for renal fibrosis, so the development of new anti-fibrotic agents is urgently needed. Accumulating evidence suggest that oxidative stress and endoplasmic reticulum (ER) stress play a critical role in renal fibrosis. Carnosol (CS) is a bioactive diterpene compound present in rosemary plants and has potent antioxidant and anti-inflammatory properties. In this study, we investigated the potential effects of CS on renal injury and fibrosis in a murine model of unilateral ureteral obstruction (UUO). Male C57BL/6J mice underwent sham or UUO surgery and received intraperitoneal injections of CS (50 mg/kg) daily for 8 consecutive days. CS improved renal function and ameliorated renal tubular injury and interstitial fibrosis in UUO mice. It suppressed oxidative injury by inhibiting pro-oxidant enzymes and activating antioxidant enzymes. Activation of ER stress was also attenuated by CS. In addition, CS inhibited apoptotic and necroptotic cell death in kidneys of UUO mice. Furthermore, cytokine production and immune cell infiltration were alleviated by CS. Taken together, these findings indicate that CS can attenuate renal injury and fibrosis in the UUO model.
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26
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Navarro-Betancourt JR, Cybulsky AV. The IRE1α pathway in glomerular diseases: The unfolded protein response and beyond. FRONTIERS IN MOLECULAR MEDICINE 2022; 2:971247. [PMID: 39086958 PMCID: PMC11285563 DOI: 10.3389/fmmed.2022.971247] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 09/07/2022] [Indexed: 08/02/2024]
Abstract
Endoplasmic reticulum (ER) function is vital for protein homeostasis ("proteostasis"). Protein misfolding in the ER of podocytes (glomerular visceral epithelial cells) is an important contributor to the pathogenesis of human glomerular diseases. ER protein misfolding causes ER stress and activates a compensatory signaling network called the unfolded protein response (UPR). Disruption of the UPR, in particular deletion of the UPR transducer, inositol-requiring enzyme 1α (IRE1α) in mouse podocytes leads to podocyte injury and albuminuria in aging, and exacerbates injury in glomerulonephritis. The UPR may interact in a coordinated manner with autophagy to relieve protein misfolding and its consequences. Recent studies have identified novel downstream targets of IRE1α, which provide new mechanistic insights into proteostatic pathways. Novel pathways of IRE1α signaling involve reticulophagy, mitochondria, metabolism, vesicular trafficking, microRNAs, and others. Mechanism-based therapies for glomerulopathies are limited, and development of non-invasive ER stress biomarkers, as well as targeting ER stress with pharmacological compounds may represent a therapeutic opportunity for preventing or attenuating progression of chronic kidney disease.
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Affiliation(s)
| | - Andrey V. Cybulsky
- Department of Medicine, McGill University Health Centre Research Institute, McGill University, Montreal, QC, Canada
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27
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Li X, Bai Y, Zhu W, Shi X, Xu S. The endoplasmic reticulum-mitochondrial crosstalk is involved in the mitigation mechanism of eucalyptol on imidacloprid toxicity in Ctenopharyngodon idellus kidney cells. FISH & SHELLFISH IMMUNOLOGY 2022; 127:99-108. [PMID: 35709895 DOI: 10.1016/j.fsi.2022.06.014] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 06/08/2022] [Accepted: 06/09/2022] [Indexed: 06/15/2023]
Abstract
Imidacloprid (IMI), a systemic neonicotinoid insecticide widely used in agriculture, resulting in persistence in aquatic environments that threaten the survival of organisms. Eucalyptol (EUC), a monoterpenoid found in plants, can be applied to medicine, food, and aquaculture. However, the potential protective effects of EUC on cell damage under neonicotinoid pesticide toxicity, and the role of ER stress and its mediated apoptosis and necroptosis in it, remain unclear. Therefore, we treated Ctenopharyngodon idellus kidney (CIK) cells with 20 mg/L IMI and 20 μM EUC for 48 h. The results showed that IMI exposure caused a higher GRP78 levels, activated ATF6, PERK-eIF2α and IRE1-XBP1 pathways, led to the decline of ATPase activities and ATP content, induced the expression of cytokine (TNF-α, IL-1β, IL-6 and INF-γ), triggered BCL2/BAX-mediated apoptosis and RIP1/RIP3/MLKL-dependent necroptosis in the CIK cell line. Surprisingly, EUC had an effect against IMI-induced cytotoxicity, showing that it effectively mitigated the above-mentioned IMI-exposure-induced changes. Taken together, these results suggested that EUC could alleviated IMI-induced cell death and dysimmunity by recovering ER stress/mitochondria imbalance. These results partly explained the mechanism of biological threat on fish under IMI exposure and the potential application value of EUC in aquaculture.
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Affiliation(s)
- Xiaojing Li
- College of Animal Science and Technology, Northeast Agricultural University, Harbin, 150030, PR China
| | - Yichen Bai
- College of Animal Science and Technology, Northeast Agricultural University, Harbin, 150030, PR China
| | - Wenjing Zhu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China
| | - Xu Shi
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China
| | - Shiwen Xu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China.
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28
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Shu Z, Chen S, Xiang H, Wu R, Wang X, Ouyang J, Zhang J, Liu H, Chen AF, Lu H. AKT/PACS2 Participates in Renal Vascular Hyperpermeability by Regulating Endothelial Fatty Acid Oxidation in Diabetic Mice. Front Pharmacol 2022; 13:876937. [PMID: 35865947 PMCID: PMC9294407 DOI: 10.3389/fphar.2022.876937] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 06/16/2022] [Indexed: 11/13/2022] Open
Abstract
Diabetes is a chronic metabolic disorder that can cause many microvascular and macrovascular complications, including diabetic nephropathy. Endothelial cells exhibit phenotypic and metabolic diversity and are affected by metabolic disorders. Whether changes in endothelial cell metabolism affect vascular endothelial function in diabetic nephropathy remains unclear. In diabetic mice, increased renal microvascular permeability and fibrosis, as well as increased MAMs and PACS2 in renal endothelial cells, were observed. Mice lacking PACS2 improved vascular leakage and glomerulosclerosis under high fat diet. In vitro, PACS2 expression, VE-cadherin internalization, fibronectin production, and Smad-2 phosphorylation increased in HUVECs treated with high glucose and palmitic acid (HGHF). Pharmacological inhibition of AKT significantly reduced HGHF-induced upregulation of PACS2 and p-Smad2 expression. Blocking fatty acid β-oxidation (FAO) ameliorated the impaired barrier function mediated by HGHF. Further studies observed that HGHF induced decreased FAO, CPT1α expression, ATP production, and NADPH/NADP+ ratio in endothelial cells. However, these changes in fatty acid metabolism were rescued by silencing PACS2. In conclusion, PACS2 participates in renal vascular hyperpermeability and glomerulosclerosis by regulating the FAO of diabetic mice. Targeting PACS2 is potential new strategy for the treatment of diabetic nephropathy.
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Affiliation(s)
- Zhihao Shu
- Health Management Center, Third Xiangya Hospital of Central South University, Changsha, China
- Department of Cardiology, Third Xiangya Hospital of Central South University, Changsha, China
| | - Shuhua Chen
- Department of Biochemistry, School of Life Sciences, Central South University, Changsha, China
| | - Hong Xiang
- Center for Experimental Medicine, Third Xiangya Hospital of Central South University, Changsha, China
| | - Ruoru Wu
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Xuewen Wang
- Department of Cardiology, Third Xiangya Hospital of Central South University, Changsha, China
| | - Jie Ouyang
- Department of Cardiology, Third Xiangya Hospital of Central South University, Changsha, China
| | - Jing Zhang
- Department of Cardiology, Third Xiangya Hospital of Central South University, Changsha, China
| | - Huiqin Liu
- Department of Cardiology, Third Xiangya Hospital of Central South University, Changsha, China
| | - Alex F. Chen
- Institute for Cardiovascular Development and Regenerative Medicine, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Hongwei Lu
- Health Management Center, Third Xiangya Hospital of Central South University, Changsha, China
- Department of Cardiology, Third Xiangya Hospital of Central South University, Changsha, China
- *Correspondence: Hongwei Lu,
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29
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Miao C, Zhu X, Wei X, Long M, Jiang L, Li C, Jin D, Du Y. Pro- and anti-fibrotic effects of vascular endothelial growth factor in chronic kidney diseases. Ren Fail 2022; 44:881-892. [PMID: 35618410 PMCID: PMC9154791 DOI: 10.1080/0886022x.2022.2079528] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Renal fibrosis is the inevitable common end-point of all progressive chronic kidney diseases. The underlying mechanisms of renal fibrosis are complex, and currently there is no effective therapy against renal fibrosis. Renal microvascular rarefaction contributes to the progression of renal fibrosis; however, an imbalance between proangiogenic and antiangiogenic factors leads to the loss of renal microvasculature. Vascular endothelial growth factor (VEGF) is the most important pro-angiogenic factor. Recent studies have unraveled the involvement of VEGF in the regulation of renal microvascular rarefaction and fibrosis via various mechanisms; however, it is not clear whether it has anti-fibrotic or pro-fibrotic effect. This paper reviews the available evidence pertaining to the function of VEGF in the fibrotic process and explores the associated underlying mechanisms. Our synthesis will help identify the future research priorities for developing specialized treatments for alleviating or preventing renal fibrosis. Abbreviation: VEGF: vascular endothelial growth factor; CKD: chronic kidney disease; ESKD: end-stage kidney disease; ER: endoplasmic reticulum; VEGFR: vascular endothelial growth factor receptor; AKI: acute kidney injury; EMT: epithelial-to-mesenchymal transition; HIF: hypoxia-inducible factor; α-SMA: α smooth muscle actin; UUO: unilateral ureteral obstruction; TGF-β: transforming growth factor-β; PMT: pericyte-myofibroblast transition; NO: nitric oxide; NOS: nitric oxide synthase; nNOS: neuronal nitric oxide synthase; iNOS: inducible nitric oxide synthase; eNOS: endothelial nitric oxide synthase; sGC: soluble guanylate cyclase; PKG: soluble guanylate cyclase dependent protein kinases; UP R: unfolded protein response
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Affiliation(s)
- Changxiu Miao
- Department of Nephrology, The First Hospital of Jilin University, Changchun, People's Republic of China
| | - Xiaoyu Zhu
- Department of Nephrology, The First Hospital of Jilin University, Changchun, People's Republic of China
| | - Xuejiao Wei
- Department of Nephrology, The First Hospital of Jilin University, Changchun, People's Republic of China
| | - Mengtuan Long
- Department of Nephrology, The First Hospital of Jilin University, Changchun, People's Republic of China
| | - Lili Jiang
- Physical Examination Center, The First Hospital of Jilin University, Changchun, People's Republic of China
| | - Chenhao Li
- Department of Nephrology, The First Hospital of Jilin University, Changchun, People's Republic of China
| | - Die Jin
- Department of Nephrology, The First Hospital of Jilin University, Changchun, People's Republic of China
| | - Yujun Du
- Department of Nephrology, The First Hospital of Jilin University, Changchun, People's Republic of China
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30
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Li S, Kong J, Yu L, Liu Q. Abnormally decreased renal Klotho is linked to endoplasmic reticulum-associated degradation in mice. Int J Med Sci 2022; 19:321-330. [PMID: 35165517 PMCID: PMC8795804 DOI: 10.7150/ijms.68137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Accepted: 12/22/2021] [Indexed: 11/16/2022] Open
Abstract
Aim: Endoplasmic reticulum-associated degradation (ERAD), which involves degradation of improperly folded proteins retained in the ER, is implicated in various diseases including chronic kidney disease. This study is aimed to determine the role of ERAD in Klotho deficiency of mice and human kidney tubular epithelial cells (HK-2) with renal interstitial fibrosis (RIF). Methods: Following establishment of a mouse RIF model by unilateral ureteral obstruction (UUO), a specific ERAD inhibitor, Eeyarestatin I (EerI), was administered to experimental animals by intraperitoneal injection. Serum and kidney samples were collected for analysis 10 days after operation. Soluble Klotho levels were measured by enzyme-linked immunosorbent assay, while the degree of kidney injury was assessed by renal histopathology. Renal Klotho expression was determined by quantitative real-time PCR, immunohistochemical and western blotting analyses. ERAD and unfolded protein response (UPR) were evaluated by detecting associated components such as Derlin-1, glucose-regulated protein 78 (GRP78), activating transcription factor 4 (ATF4) and protein disulfide isomerase (PDI). HK-2 cells were exposed to transforming growth factor (TGF)-β1 with or without EerI, and expressions of related proteins including Klotho, Derlin-1, GRP78, ATF4 and PDI were determined by western blotting analyses. Results: UUO induced severe kidney injuries and RIF. Klotho expression in both serum and kidney tissue was obviously downregulated, while Derlin-1 was notably upregulated, indicating that ERAD was activated to potentially degrade improperly folded Klotho protein in this model. Intriguingly, treatment with EerI led to significantly increased Klotho expression, especially soluble (functional) Klotho. Furthermore, specific inhibition of ERAD increased expression of GRP78, ATF4 and PDI compared with the UUO group. The consistent results in vitro were also obtained in TGF-β1-treated HK-2 cells exposed to EerI. These observations suggest that UPR was remarkably enhanced in the presence of ERAD inhibition and compensated for excess improperly folded proteins, subsequently contributing to the additional production of mature Klotho protein. Conclusion: ERAD is involved in Klotho deficiency in RIF and its specific inhibition significantly promoted Klotho expression, possibly through enhanced UPR. This may represent a novel regulatory mechanism and new therapeutic target for reversing Klotho deficiency.
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Affiliation(s)
- ShaSha Li
- Clinical Research & Lab Centre, Affiliated Kunshan Hospital of Jiangsu University, 91 Qianjin West Road, Kunshan, Jiangsu, 215300, China
| | - JiaWei Kong
- Department of Nephrology, Affiliated Kunshan Hospital of Jiangsu University, 91 Qianjin West Road, Kunshan, Jiangsu, 215300, China
| | - LiXia Yu
- Department of Nephrology, Affiliated Kunshan Hospital of Jiangsu University, 91 Qianjin West Road, Kunshan, Jiangsu, 215300, China
| | - QiFeng Liu
- Department of Nephrology, Affiliated Kunshan Hospital of Jiangsu University, 91 Qianjin West Road, Kunshan, Jiangsu, 215300, China
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Ajoolabady A, Wang S, Kroemer G, Klionsky DJ, Uversky VN, Sowers JR, Aslkhodapasandhokmabad H, Bi Y, Ge J, Ren J. ER Stress in Cardiometabolic Diseases: From Molecular Mechanisms to Therapeutics. Endocr Rev 2021; 42:839-871. [PMID: 33693711 DOI: 10.1210/endrev/bnab006] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Indexed: 02/08/2023]
Abstract
The endoplasmic reticulum (ER) hosts linear polypeptides and fosters natural folding of proteins through ER-residing chaperones and enzymes. Failure of the ER to align and compose proper protein architecture leads to accumulation of misfolded/unfolded proteins in the ER lumen, which disturbs ER homeostasis to provoke ER stress. Presence of ER stress initiates the cytoprotective unfolded protein response (UPR) to restore ER homeostasis or instigates a rather maladaptive UPR to promote cell death. Although a wide array of cellular processes such as persistent autophagy, dysregulated mitophagy, and secretion of proinflammatory cytokines may contribute to the onset and progression of cardiometabolic diseases, it is well perceived that ER stress also evokes the onset and development of cardiometabolic diseases, particularly cardiovascular diseases (CVDs), diabetes mellitus, obesity, and chronic kidney disease (CKD). Meanwhile, these pathological conditions further aggravate ER stress, creating a rather vicious cycle. Here in this review, we aimed at summarizing and updating the available information on ER stress in CVDs, diabetes mellitus, obesity, and CKD, hoping to offer novel insights for the management of these cardiometabolic comorbidities through regulation of ER stress.
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Affiliation(s)
- Amir Ajoolabady
- University of Wyoming College of Health Sciences, Laramie, Wyoming 82071, USA
| | - Shuyi Wang
- University of Wyoming College of Health Sciences, Laramie, Wyoming 82071, USA
- School of Medicine Shanghai University, Shanghai 200444, China
| | - Guido Kroemer
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France
- Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France
- Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France
- Suzhou Institute for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China
- Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden
| | - Daniel J Klionsky
- Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109, USA
| | - Vladimir N Uversky
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, USA
| | - James R Sowers
- Dalton and Diabetes and Cardiovascular Center, University of Missouri Columbia, Columbia, Missouri 65212, USA
| | | | - Yaguang Bi
- Shanghai Institute of Cardiovascular Diseases, Department of Cardiology, Zhongshan Hospital Fudan University, Shanghai 200032, China
| | - Junbo Ge
- Shanghai Institute of Cardiovascular Diseases, Department of Cardiology, Zhongshan Hospital Fudan University, Shanghai 200032, China
| | - Jun Ren
- University of Wyoming College of Health Sciences, Laramie, Wyoming 82071, USA
- Shanghai Institute of Cardiovascular Diseases, Department of Cardiology, Zhongshan Hospital Fudan University, Shanghai 200032, China
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington 98195, USA
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32
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Taguchi K, Elias BC, Krystofiak E, Qian S, Sant S, Yang H, Fogo AB, Brooks CR. Quantitative super-resolution microscopy reveals promoting mitochondrial interconnectivity protects against AKI. KIDNEY360 2021; 2:1892-1907. [PMID: 35342885 PMCID: PMC8953106 DOI: 10.34067/kid.0001602021] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Background The root of many kidney diseases in humans can be traced to alterations or damage to subcellular organelles. Mitochondrial fragmentation, endoplasmic reticulum (ER) stress, and lysosomal inhibition, among others, ultimately contribute to kidney injury and are the target of therapeutics in development. Although recent technological advancements allow for the understanding of disease states at the cellular level, investigating changes in subcellular organelles from kidney tissue remains challenging. Methods Using structured illumination microscopy, we imaged mitochondria and other organelles from paraffin sections of mouse tissue and human kidney biopsy specimens. The resulting images were 3D rendered to quantify mitochondrial size, content, and morphology. Results were compared with those from transmission electron microscopy and segmentation. Results Super-resolution imaging reveals kidney tubular epithelial cell mitochondria in rodent and human kidney tissue form large, interconnected networks under basal conditions, which are fragmented with injury. This approach can be expanded to other organelles and cellular structures including autophagosomes, ER, brush border, and cell morphology. We find that, during unilateral ischemia, mitochondrial fragmentation occurs in most tubule cells, and they remain fragmented for >96 hours. Promoting mitochondrial fusion with the fusion promotor M1 preserves mitochondrial morphology and interconnectivity and protects against cisplatin-induced kidney injury. Conclusions We provide, for the first time, a nonbiased, semiautomated approach for quantification of the 3D morphology of mitochondria in kidney tissue. Maintaining mitochondrial interconnectivity and morphology protects against kidney injury. Super-resolution imaging has the potential to both drive discovery of novel pathobiologic mechanisms in kidney tissue and broaden the diagnoses that can be made on human biopsy specimens.
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Affiliation(s)
- Kensei Taguchi
- Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Bertha C. Elias
- Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Evan Krystofiak
- Cell Imaging Shared Resource, Vanderbilt University, Nashville, Tennessee
| | - Subo Qian
- Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Snehal Sant
- Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Haichun Yang
- Department of Pathology, Microbiology and immunology, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Agnes B. Fogo
- Department of Pathology, Microbiology and immunology, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Craig R. Brooks
- Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee,Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee
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Nury T, Yammine A, Ghzaiel I, Sassi K, Zarrouk A, Brahmi F, Samadi M, Rup-Jacques S, Vervandier-Fasseur D, Pais de Barros J, Bergas V, Ghosh S, Majeed M, Pande A, Atanasov A, Hammami S, Hammami M, Mackrill J, Nasser B, Andreoletti P, Cherkaoui-Malki M, Vejux A, Lizard G. Attenuation of 7-ketocholesterol- and 7β-hydroxycholesterol-induced oxiapoptophagy by nutrients, synthetic molecules and oils: Potential for the prevention of age-related diseases. Ageing Res Rev 2021; 68:101324. [PMID: 33774195 DOI: 10.1016/j.arr.2021.101324] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 03/10/2021] [Accepted: 03/12/2021] [Indexed: 12/18/2022]
Abstract
Age-related diseases for which there are no effective treatments include cardiovascular diseases; neurodegenerative diseases such as Alzheimer's disease; eye disorders such as cataract and age-related macular degeneration; and, more recently, Severe Acute Respiratory Syndrome (SARS-CoV-2). These diseases are associated with plasma and/or tissue increases in cholesterol derivatives mainly formed by auto-oxidation: 7-ketocholesterol, also known as 7-oxo-cholesterol, and 7β-hydroxycholesterol. The formation of these oxysterols can be considered as a consequence of mitochondrial and peroxisomal dysfunction, leading to increased in oxidative stress, which is accentuated with age. 7-ketocholesterol and 7β-hydroxycholesterol cause a specific form of cytotoxic activity defined as oxiapoptophagy, including oxidative stress and induction of death by apoptosis associated with autophagic criteria. Oxiaptophagy is associated with organelle dysfunction and in particular with mitochondrial and peroxisomal alterations involved in the induction of cell death and in the rupture of redox balance. As the criteria characterizing 7-ketocholesterol- and 7β-hydroxycholesterol-induced cytotoxicity are often simultaneously observed in major age-related diseases (cardiovascular diseases, age-related macular degeneration, Alzheimer's disease) the involvement of these oxysterols in the pathophysiology of the latter seems increasingly likely. It is therefore important to better understand the signalling pathways associated with the toxicity of 7-ketocholesterol and 7β-hydroxycholesterol in order to identify pharmacological targets, nutrients and synthetic molecules attenuating or inhibiting the cytotoxic activities of these oxysterols. Numerous natural cytoprotective compounds have been identified: vitamins, fatty acids, polyphenols, terpenes, vegetal pigments, antioxidants, mixtures of compounds (oils, plant extracts) and bacterial enzymes. However, few synthetic molecules are able to prevent 7-ketocholesterol- and/or 7β-hydroxycholesterol-induced cytotoxicity: dimethyl fumarate, monomethyl fumarate, the tyrosine kinase inhibitor AG126, memantine, simvastatine, Trolox, dimethylsufoxide, mangafodipir and mitochondrial permeability transition pore (MPTP) inhibitors. The effectiveness of these compounds, several of which are already in use in humans, makes it possible to consider using them for the treatment of certain age-related diseases associated with increased plasma and/or tissue levels of 7-ketocholesterol and/or 7β-hydroxycholesterol.
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