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Han YZ, Du BX, Zhu XY, Wang YZY, Zheng HJ, Liu WJ. Lipid metabolism disorder in diabetic kidney disease. Front Endocrinol (Lausanne) 2024; 15:1336402. [PMID: 38742197 PMCID: PMC11089115 DOI: 10.3389/fendo.2024.1336402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 04/09/2024] [Indexed: 05/16/2024] Open
Abstract
Diabetic kidney disease (DKD), a significant complication associated with diabetes mellitus, presents limited treatment options. The progression of DKD is marked by substantial lipid disturbances, including alterations in triglycerides, cholesterol, sphingolipids, phospholipids, lipid droplets, and bile acids (BAs). Altered lipid metabolism serves as a crucial pathogenic mechanism in DKD, potentially intertwined with cellular ferroptosis, lipophagy, lipid metabolism reprogramming, and immune modulation of gut microbiota (thus impacting the liver-kidney axis). The elucidation of these mechanisms opens new potential therapeutic pathways for DKD management. This research explores the link between lipid metabolism disruptions and DKD onset.
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Affiliation(s)
- Yi-Zhen Han
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Bo-Xuan Du
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Xing-Yu Zhu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Yang-Zhi-Yuan Wang
- School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, China
| | - Hui-Juan Zheng
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Wei-Jing Liu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
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2
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Elwakiel A, Mathew A, Isermann B. The role of endoplasmic reticulum-mitochondria-associated membranes in diabetic kidney disease. Cardiovasc Res 2024; 119:2875-2883. [PMID: 38367274 DOI: 10.1093/cvr/cvad190] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 07/03/2023] [Accepted: 07/07/2023] [Indexed: 02/19/2024] Open
Abstract
Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease worldwide. The pathomechanisms of DKD are multifactorial, yet haemodynamic and metabolic changes in the early stages of the disease appear to predispose towards irreversible functional loss and histopathological changes. Recent studies highlight the importance of endoplasmic reticulum-mitochondria-associated membranes (ER-MAMs), structures conveying important cellular homeostatic and metabolic effects, in the pathology of DKD. Disruption of ER-MAM integrity in diabetic kidneys is associated with DKD progression, but the regulation of ER-MAMs and their pathogenic contribution remain largely unknown. Exploring the cell-specific components and dynamic changes of ER-MAMs in diabetic kidneys may lead to the identification of new approaches to detect and stratify diabetic patients with DKD. In addition, these insights may lead to novel therapeutic approaches to target and/or reverse disease progression. In this review, we discuss the association of ER-MAMs with key pathomechanisms driving DKD such as insulin resistance, dyslipidaemia, ER stress, and inflammasome activation and the importance of further exploration of ER-MAMs as diagnostic and therapeutic targets in DKD.
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Affiliation(s)
- Ahmed Elwakiel
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Paul-List-Straße 13/15, 04103 Leipzig, Germany
| | - Akash Mathew
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Paul-List-Straße 13/15, 04103 Leipzig, Germany
| | - Berend Isermann
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Paul-List-Straße 13/15, 04103 Leipzig, Germany
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3
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Amirinejad A, Khayyatzadeh SS, Rezaeivandchali N, Gheibihayat SM. Efferocytosis and Metabolic Syndrome: A Narrative Review. Curr Mol Med 2024; 24:751-757. [PMID: 37431902 DOI: 10.2174/1566524023666230710120438] [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: 01/14/2023] [Revised: 06/04/2023] [Accepted: 06/05/2023] [Indexed: 07/12/2023]
Abstract
Metabolic syndrome (MetS), which is distinguished by the simultaneous presence of hyperglycemia, dyslipidemia, hypertension, and central obesity, is a critical risk factor for cardiovascular disease (CVDs), mortality, and illness burden. Eliminating about one million cells per second in the human body, apoptosis conserves homeostasis and regulates the life cycle of organisms. In the physiological condition, the apoptotic cells internalize to the phagocytes by a multistep process named efferocytosis. Any impairment in the clearance of these apoptotic cells results in conditions related to chronic inflammation, such as obesity, diabetes, and dyslipidemia. On the other hand, insulin resistance and MetS can disturb the efferocytosis process. Since no study investigated the relationship between efferocytosis and MetS, we decided to explore the different steps of efferocytosis and describe how inefficient dead cell clearance is associated with the progression of MetS.
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Affiliation(s)
- Ali Amirinejad
- Department of Nutrition, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Sayyed Saeid Khayyatzadeh
- Nutrition and Food Security Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
- Department of Nutrition, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Noushin Rezaeivandchali
- Department of Biochemistry and Genetics, Faculty of Medicine, Arak University of Medical Sciences, Arak, Iran
| | - Seyed Mohammad Gheibihayat
- Department of Medical Biotechnology, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
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Chae SY, Kim Y, Park CW. Oxidative Stress Induced by Lipotoxicity and Renal Hypoxia in Diabetic Kidney Disease and Possible Therapeutic Interventions: Targeting the Lipid Metabolism and Hypoxia. Antioxidants (Basel) 2023; 12:2083. [PMID: 38136203 PMCID: PMC10740440 DOI: 10.3390/antiox12122083] [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: 11/09/2023] [Revised: 11/26/2023] [Accepted: 12/01/2023] [Indexed: 12/24/2023] Open
Abstract
Oxidative stress, a hallmark pathophysiological feature in diabetic kidney disease (DKD), arises from the intricate interplay between pro-oxidants and anti-oxidants. While hyperglycemia has been well established as a key contributor, lipotoxicity emerges as a significant instigator of oxidative stress. Lipotoxicity encompasses the accumulation of lipid intermediates, culminating in cellular dysfunction and cell death. However, the mechanisms underlying lipotoxic kidney injury in DKD still require further investigation. The key role of cell metabolism in the maintenance of cell viability and integrity in the kidney is of paramount importance to maintain proper renal function. Recently, dysfunction in energy metabolism, resulting from an imbalance in oxygen levels in the diabetic condition, may be the primary pathophysiologic pathway driving DKD. Therefore, we aim to shed light on the pivotal role of oxidative stress related to lipotoxicity and renal hypoxia in the initiation and progression of DKD. Multifaceted mechanisms underlying lipotoxicity, including oxidative stress with mitochondrial dysfunction, endoplasmic reticulum stress activated by the unfolded protein response pathway, pro-inflammation, and impaired autophagy, are delineated here. Also, we explore potential therapeutic interventions for DKD, targeting lipotoxicity- and hypoxia-induced oxidative stress. These interventions focus on ameliorating the molecular pathways of lipid accumulation within the kidney and enhancing renal metabolism in the face of lipid overload or ameliorating subsequent oxidative stress. This review highlights the significance of lipotoxicity, renal hypoxia-induced oxidative stress, and its potential for therapeutic intervention in DKD.
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Affiliation(s)
- Seung Yun Chae
- Division of Nephrology, Department of Internal Medicine, Seoul St. Mary’s Hospital, The College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea; (S.Y.C.); (Y.K.)
| | - Yaeni Kim
- Division of Nephrology, Department of Internal Medicine, Seoul St. Mary’s Hospital, The College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea; (S.Y.C.); (Y.K.)
| | - Cheol Whee Park
- Division of Nephrology, Department of Internal Medicine, Seoul St. Mary’s Hospital, The College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea; (S.Y.C.); (Y.K.)
- Institute for Aging and Metabolic Disease, Seoul St. Mary’s Hospital, The College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea
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Hsu CC, Fidler TP, Kanter JE, Kothari V, Kramer F, Tang J, Tall AR, Bornfeldt KE. Hematopoietic NLRP3 and AIM2 Inflammasomes Promote Diabetes-Accelerated Atherosclerosis, but Increased Necrosis Is Independent of Pyroptosis. Diabetes 2023; 72:999-1011. [PMID: 37083999 PMCID: PMC10281813 DOI: 10.2337/db22-0962] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 04/15/2023] [Indexed: 04/22/2023]
Abstract
Serum apolipoprotein C3 (APOC3) predicts incident cardiovascular events in people with type 1 diabetes, and silencing of APOC3 prevents both lesion initiation and advanced lesion necrotic core expansion in a mouse model of type 1 diabetes. APOC3 acts by slowing the clearance of triglyceride-rich lipoproteins, but lipid-free APOC3 has recently been reported to activate an inflammasome pathway in monocytes. We therefore investigated the contribution of hematopoietic inflammasome pathways to atherosclerosis in mouse models of type 1 diabetes. LDL receptor-deficient diabetes mouse models were transplanted with bone marrow from donors deficient in NOD, LRR and pyrin domain-containing protein 3 (NLRP3), absent in melanoma 2 (AIM2) or gasdermin D (GSDMD), an inflammasome-induced executor of pyroptotic cell death. Mice with diabetes exhibited inflammasome activation and consistently, increased plasma interleukin-1β (IL-1β) and IL-18. Hematopoietic deletions of NLRP3, AIM2, or GSDMD caused smaller atherosclerotic lesions in diabetic mice. The increased lesion necrotic core size in diabetic mice was independent of macrophage pyroptosis because hematopoietic GSDMD deficiency failed to prevent necrotic core expansion in advanced lesions. Our findings demonstrate that AIM2 and NLRP3 inflammasomes contribute to atherogenesis in diabetes and suggest that necrotic core expansion is independent of macrophage pyroptosis. ARTICLE HIGHLIGHTS The contribution of hematopoietic cell inflammasome activation to atherosclerosis associated with type 1 diabetes is unknown. The goal of this study was to address whether hematopoietic NOD, LRR, and pyrin domain-containing protein 3 (NLRP3), absent in melanoma 2 (AIM2) inflammasomes, or the pyroptosis executioner gasdermin D (GSDMD) contributes to atherosclerosis in mouse models of type 1 diabetes. Diabetic mice exhibited increased inflammasome activation, with hematopoietic deletions of NLRP3, AIM2, or GSDMD causing smaller atherosclerotic lesions in diabetic mice, but the increased lesion necrotic core size in diabetic mice was independent of macrophage pyroptosis. Further studies on whether inflammasome activation contributes to cardiovascular complications in people with type 1 diabetes are warranted.
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Affiliation(s)
- Cheng-Chieh Hsu
- Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington Medicine Diabetes Institute, University of Washington, Seattle, WA
| | - Trevor P. Fidler
- Division of Molecular Medicine, Department of Medicine, Columbia University Irving Medical Center, New York, NY
| | - Jenny E. Kanter
- Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington Medicine Diabetes Institute, University of Washington, Seattle, WA
| | - Vishal Kothari
- Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington Medicine Diabetes Institute, University of Washington, Seattle, WA
| | - Farah Kramer
- Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington Medicine Diabetes Institute, University of Washington, Seattle, WA
| | - Jingjing Tang
- Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington Medicine Diabetes Institute, University of Washington, Seattle, WA
| | - Alan R. Tall
- Division of Molecular Medicine, Department of Medicine, Columbia University Irving Medical Center, New York, NY
| | - Karin E. Bornfeldt
- Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington Medicine Diabetes Institute, University of Washington, Seattle, WA
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Cervantes J, Kanter JE. Monocyte and macrophage foam cells in diabetes-accelerated atherosclerosis. Front Cardiovasc Med 2023; 10:1213177. [PMID: 37378396 PMCID: PMC10291141 DOI: 10.3389/fcvm.2023.1213177] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 05/30/2023] [Indexed: 06/29/2023] Open
Abstract
Diabetes results in an increased risk of atherosclerotic cardiovascular disease. This minireview will discuss whether monocyte and macrophage lipid loading contribute to this increased risk, as monocytes and macrophages are critically involved in the progression of atherosclerosis. Both uptake and efflux pathways have been described as being altered by diabetes or conditions associated with diabetes, which may contribute to the increased accumulation of lipids seen in macrophages in diabetes. More recently, monocytes have also been described as lipid-laden in response to elevated lipids, including triglyceride-rich lipoproteins, the class of lipids often elevated in the setting of diabetes.
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Affiliation(s)
| | - Jenny E. Kanter
- Department of Medicine, UW Medicine Diabetes Institute, University of Washington, Seattle, WA, United States
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Njeim R, Alkhansa S, Fornoni A. Unraveling the Crosstalk between Lipids and NADPH Oxidases in Diabetic Kidney Disease. Pharmaceutics 2023; 15:pharmaceutics15051360. [PMID: 37242602 DOI: 10.3390/pharmaceutics15051360] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 04/25/2023] [Accepted: 04/25/2023] [Indexed: 05/28/2023] Open
Abstract
Diabetic kidney disease (DKD) is a serious complication of diabetes mellitus and a leading cause of end-stage renal disease. Abnormal lipid metabolism and intrarenal accumulation of lipids have been shown to be strongly correlated with the development and progression of diabetic kidney disease (DKD). Cholesterol, phospholipids, triglycerides, fatty acids, and sphingolipids are among the lipids that are altered in DKD, and their renal accumulation has been linked to the pathogenesis of the disease. In addition, NADPH oxidase-induced production of reactive oxygen species (ROS) plays a critical role in the development of DKD. Several types of lipids have been found to be tightly linked to NADPH oxidase-induced ROS production. This review aims to explore the interplay between lipids and NADPH oxidases in order to provide new insights into the pathogenesis of DKD and identify more effective targeted therapies for the disease.
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Affiliation(s)
- Rachel Njeim
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33136, USA
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Sahar Alkhansa
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107-2020, Lebanon
- AUB Diabetes, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Alessia Fornoni
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33136, USA
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA
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Hagmann H, Khayyat NH, Oezel C, Papadakis A, Kuczkowski A, Benzing T, Gulbins E, Dryer S, Brinkkoetter PT. Paraoxonase 2 (PON2) Deficiency Reproduces Lipid Alterations of Diabetic and Inflammatory Glomerular Disease and Affects TRPC6 Signaling. Cells 2022; 11:cells11223625. [PMID: 36429053 PMCID: PMC9688324 DOI: 10.3390/cells11223625] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 10/31/2022] [Accepted: 11/11/2022] [Indexed: 11/18/2022] Open
Abstract
Diabetes and inflammatory diseases are associated with an altered cellular lipid composition due to lipid peroxidation. The pathogenic potential of these lipid alterations in glomerular kidney diseases remains largely obscure as suitable cell culture and animal models are lacking. In glomerular disease, a loss of terminally differentiated glomerular epithelial cells called podocytes refers to irreversible damage. Podocytes are characterized by a complex ramified cellular architecture and highly active transmembrane signaling. Alterations in lipid composition in states of disease have been described in podocytes but the pathophysiologic mechanisms mediating podocyte damage are unclear. In this study, we employ a genetic deletion of the anti-oxidative, lipid-modifying paraoxonase 2 enzyme (PON2) as a model to study altered cellular lipid composition and its effects on cellular signaling in glomerular disease. PON2 deficiency reproduces features of an altered lipid composition of glomerular disease, characterized by an increase in ceramides and cholesterol. PON2 knockout mice are more susceptible to glomerular damage in models of aggravated oxidative stress such as adriamycin-induced nephropathy. Voltage clamp experiments in cultured podocytes reveal a largely increased TRPC6 conductance after a membrane stretch in PON2 deficiency. Correspondingly, a concomitant knockout of TRPC6 and PON2 partially rescues the aggravated glomerular phenotype of a PON2 knockout in the adriamycin model. This study establishes PON2 deficiency as a model to investigate the pathophysiologic mechanisms of podocyte dysfunction related to alterations in the lipid composition, as seen in diabetic and inflammatory glomerular disease. Expanding the knowledge on these routes and options of intervention could lead to novel treatment strategies for glomerular disease.
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Affiliation(s)
- Henning Hagmann
- Department II of Internal Medicine, University of Cologne, Faculty of Medicine and University Hospital Cologne, 50937 Cologne, Germany
- Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine, University Hospital Cologne, 50931 Cologne, Germany
- Correspondence:
| | | | - Cem Oezel
- Department II of Internal Medicine, University of Cologne, Faculty of Medicine and University Hospital Cologne, 50937 Cologne, Germany
- Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine, University Hospital Cologne, 50931 Cologne, Germany
| | - Antonios Papadakis
- Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine, University Hospital Cologne, 50931 Cologne, Germany
- Institute for Genetics, Faculty of Mathematics and Natural Sciences, University of Cologne, 50931 Cologne, Germany
| | - Alexander Kuczkowski
- Department II of Internal Medicine, University of Cologne, Faculty of Medicine and University Hospital Cologne, 50937 Cologne, Germany
- Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine, University Hospital Cologne, 50931 Cologne, Germany
| | - Thomas Benzing
- Department II of Internal Medicine, University of Cologne, Faculty of Medicine and University Hospital Cologne, 50937 Cologne, Germany
- Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine, University Hospital Cologne, 50931 Cologne, Germany
- Cologne Cluster of Excellence on Cellular Stress Responses in Ageing-Associated Diseases (CECAD) and Systems Biology of Ageing Cologne (Sybacol), 50931 Cologne, Germany
| | - Erich Gulbins
- Department of Molecular Biology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany
| | - Stuart Dryer
- Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA
- Department of Biomedical Sciences, Tilman J. Fertitta Family College of Medicine, University of Houston, Houston, TX 77204, USA
| | - Paul T. Brinkkoetter
- Department II of Internal Medicine, University of Cologne, Faculty of Medicine and University Hospital Cologne, 50937 Cologne, Germany
- Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine, University Hospital Cologne, 50931 Cologne, Germany
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Zhao C, Li L, Li C, Tang C, Cai J, Liu Y, Yang J, Xi Y, Yang M, Jiang N, Han Y, Liu Y, Luo S, Xiao L, Sun L. PACS-2 deficiency in tubular cells aggravates lipid-related kidney injury in diabetic kidney disease. Mol Med 2022; 28:117. [PMID: 36138342 PMCID: PMC9502582 DOI: 10.1186/s10020-022-00545-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 09/09/2022] [Indexed: 11/18/2022] Open
Abstract
Background Lipid accumulation in tubular cells plays a key role in diabetic kidney disease (DKD). Targeting lipid metabolism disorders has clinical value in delaying the progression of DKD, but the precise mechanism by which molecules mediate lipid-related kidney injury remains unclear. Phosphofurin acidic cluster sorting protein 2 (PACS-2) is a multifunctional sorting protein that plays a role in lipid metabolism. This study determined the role of PACS-2 in lipid-related kidney injury in DKD. Methods Diabetes was induced by a high-fat diet combined with intraperitoneal injections of streptozotocin (HFD/STZ) in proximal tubule-specific knockout of Pacs-2 mice (PT-Pacs-2−/− mice) and the control mice (Pacs-2fl/fl mice). Transcriptomic analysis was performed between Pacs-2fl/fl mice and PT-Pacs-2−/− mice. Results Diabetic PT-Pacs-2−/− mice developed more severe tubule injury and proteinuria compared to diabetic Pacs-2fl/fl mice, which accompanied with increasing lipid synthesis, uptake and decreasing cholesterol efflux as well as lipid accumulation in tubules of the kidney. Furthermore, transcriptome analysis showed that the mRNA level of sterol O-acyltransferase 1 (Soat1) was up-regulated in the kidney of control PT-Pacs-2−/− mice. Transfection of HK2 cells with PACS-2 siRNA under high glucose plus palmitic acid (HGPA) condition aggravated lipid deposition and increased the expression of SOAT1 and sterol regulatory element-binding proteins (SREBPs), while the effect was blocked partially in that of co-transfection of SOAT1 siRNA. Conclusions PACS-2 has a protective role against lipid-related kidney injury in DKD through SOAT1/SREBPs signaling. Supplementary Information The online version contains supplementary material available at 10.1186/s10020-022-00545-x.
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Affiliation(s)
- Chanyue Zhao
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital, Central South University, No.139 Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Li Li
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital, Central South University, No.139 Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Chenrui Li
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital, Central South University, No.139 Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Chengyuan Tang
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital, Central South University, No.139 Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Juan Cai
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital, Central South University, No.139 Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Yu Liu
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital, Central South University, No.139 Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Jinfei Yang
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital, Central South University, No.139 Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Yiyun Xi
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital, Central South University, No.139 Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Ming Yang
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital, Central South University, No.139 Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Na Jiang
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital, Central South University, No.139 Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Yachun Han
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital, Central South University, No.139 Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Yan Liu
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital, Central South University, No.139 Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Shilu Luo
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital, Central South University, No.139 Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Li Xiao
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital, Central South University, No.139 Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Lin Sun
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital, Central South University, No.139 Renmin Middle Road, Changsha, 410011, Hunan, China.
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10
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Tian F, Chen H, Zhang J, He W. Reprogramming Metabolism of Macrophages as a Target for Kidney Dysfunction Treatment in Autoimmune Diseases. Int J Mol Sci 2022; 23:8024. [PMID: 35887371 PMCID: PMC9316004 DOI: 10.3390/ijms23148024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 07/13/2022] [Accepted: 07/18/2022] [Indexed: 12/04/2022] Open
Abstract
Chronic kidney disease (CKD), as one of the main complications of many autoimmune diseases, is difficult to cure, which places a huge burden on patients' health and the economy and poses a great threat to human health. At present, the mainstream view is that autoimmune diseases are a series of diseases and complications caused by immune cell dysfunction leading to the attack of an organism's tissues by its immune cells. The kidney is the organ most seriously affected by autoimmune diseases as it has a very close relationship with immune cells. With the development of an in-depth understanding of cell metabolism in recent years, an increasing number of scientists have discovered the metabolic changes in immune cells in the process of disease development, and we have a clearer understanding of the characteristics of the metabolic changes in immune cells. This suggests that the regulation of immune cell metabolism provides a new direction for the treatment and prevention of kidney damage caused by autoimmune diseases. Macrophages are important immune cells and are a double-edged sword in the repair process of kidney injury. Although they can repair damaged kidney tissue, over-repair will also lead to the loss of renal structural reconstruction function. In this review, from the perspective of metabolism, the metabolic characteristics of macrophages in the process of renal injury induced by autoimmune diseases are described, and the metabolites that can regulate the function of macrophages are summarized. We believe that treating macrophage metabolism as a target can provide new ideas for the treatment of the renal injury caused by autoimmune diseases.
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Affiliation(s)
- Feng Tian
- Department of Immunology, CAMS Key Laboratory T Cell and Cancer Immunotherapy, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Medical Molecular Biology, Beijing 100005, China
| | - Hui Chen
- Department of Immunology, CAMS Key Laboratory T Cell and Cancer Immunotherapy, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Medical Molecular Biology, Beijing 100005, China
- Haihe Laboratory of Cell Ecosystem, Tianjin 100730, China
| | - Jianmin Zhang
- Department of Immunology, CAMS Key Laboratory T Cell and Cancer Immunotherapy, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Medical Molecular Biology, Beijing 100005, China
- Haihe Laboratory of Cell Ecosystem, Tianjin 100730, China
| | - Wei He
- Department of Immunology, CAMS Key Laboratory T Cell and Cancer Immunotherapy, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Medical Molecular Biology, Beijing 100005, China
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Kanbay M, Copur S, Demiray A, Sag AA, Covic A, Ortiz A, Tuttle KR. Fatty kidney: A possible future for chronic kidney disease research. Eur J Clin Invest 2022; 52:e13748. [PMID: 35040119 DOI: 10.1111/eci.13748] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Revised: 01/15/2022] [Accepted: 01/16/2022] [Indexed: 12/01/2022]
Abstract
BACKGROUND Metabolic syndrome is a growing twenty-first century pandemic associated with multiple clinical comorbidities ranging from cardiovascular diseases, non-alcoholic fatty liver disease and polycystic ovary syndrome to kidney dysfunction. A novel area of research investigates the concept of fatty kidney in the pathogenesis of chronic kidney disease, especially in patients with diabetes mellitus or metabolic syndrome. AIM To review the most updated literature on fatty kidney and provide future research, diagnostic and therapeutic perspectives on a disease increasingly affecting the contemporary world. MATERIALS AND METHOD We performed an extensive literature search through three databases including Embase (Elsevier) and the Cochrane Central Register of Controlled Trials (Wiley) and PubMed/Medline Web of Science in November 2021 by using the following terms and their combinations: 'fatty kidney', 'ectopic fat', 'chronic kidney disease', 'cardiovascular event', 'cardio-metabolic risk', 'albuminuria' and 'metabolic syndrome'. Each study has been individually assessed by the authors. RESULTS Oxidative stress and inflammation, Klotho deficiency, endoplasmic reticulum stress, mitochondrial dysfunction and disruption of cellular energy balance appear to be the main pathophysiological mechanisms leading to tissue damage following fat accumulation. Despite the lack of large-scale comprehensive studies in this novel field of research, current clinical trials demonstrate fatty kidney as an independent risk factor for the development of chronic kidney disease and cardiovascular events. CONCLUSION The requirement for future studies investigating the pathophysiology, clinical outcomes and therapeutics of fatty kidney is clear.
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Affiliation(s)
- Mehmet Kanbay
- Division of Nephrology, Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Sidar Copur
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Atalay Demiray
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Alan A Sag
- Division of Vascular and Interventional Radiology, Department of Radiology, Duke University Medical Center, Durham, North Carolina, USA
| | - Adrian Covic
- Department of Nephrology, Grigore T. Popa' University of Medicine, Iasi, Romania
| | - Alberto Ortiz
- Department of Medicine, Universidad Autonoma de Madrid and IIS-Fundacion Jimenez Diaz, Madrid, Spain
| | - Kathherine R Tuttle
- Division of Nephrology, University of Washington, Seattle, Washington, USA.,Providence Medical Research Center, Providence Health Care, Spokane, Washington, USA
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12
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Ghaffari T, Moradi N, Chamani E, Ebadi Z, Fadaei R, Alizadeh-Fanalou S, Yarahmadi S, Fallah S. Captopril and Spironolactone Can Attenuate Diabetic Nephropathy in Wistar Rats by Targeting ABCA1 and microRNA-33. Curr Pharm Des 2022; 28:1367-1372. [DOI: 10.2174/1381612828666220401143249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 02/24/2022] [Indexed: 11/22/2022]
Abstract
Background:
Nephropathy diabetes is one of the important causes of death and a more prevalent cause of end-stage renal disease.
Objective:
The present study investigated the effect of applying spironolactone and captopril and their combination on some renal performance indices and cholesterol-efflux-related gene expression in nephropathy diabetic rats.
Methods:
Intraperitoneal injection of streptozotocin was used to induce diabetes in rats. FBS, creatinine, and BUN were assayed using the calorimetry technique; also, urine microalbumin was assayed by ELISA. Hepatic gene expressions of ABCA1, ABCG1, and miR-33 were evaluated by the real-time PCR method.
Results:
FBS levels in the captopril-treated group were significantly decreased compared with the untreated diabetic group. BUN levels of treated groups with captopril and a combination of captopril + spironolactone were significantly increased. GFR of both treated diabetic groups with captopril and spironolactone was significantly lower than an untreated diabetic group. ABCA1 gene expression in hepatic cells of the combination of spironolactone + captopril treated group was significantly increased compared to other treated and untreated diabetic groups. The hepatic expression of the ABCG1 gene in the treated and untreated diabetic groups was significantly lower than in the control group. Treatment of the diabetic group with only combination therapy decreased the hepatic gene expression of miR-33 significantly.
Conclusion:
Obtained results suggest that S+C combination therapy can improve nephropathy and diabetes disorders by targeting the ABCA1 and miR-33 gene expression. It is suggested miR-33 and ABCA1 genes evaluation could be a new therapeutic strategy for nephropathy diabetes remediation.
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Affiliation(s)
- Tina Ghaffari
- Department of Biochemistry and Nutrition, School of Medicine Iran University of Medical Sciences
| | - Nariman Moradi
- Department of Clinical Biochemistry, School of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Elham Chamani
- Department of Clinical Biochemistry, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Zahra Ebadi
- Department of Biochemistry and Nutrition, School of Medicine Iran University of Medical Sciences
| | - Reza Fadaei
- Sleep Disorders Research Center, Research Institute for Health, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Shahin Alizadeh-Fanalou
- Department of Biochemistry and Nutrition, School of Medicine Iran University of Medical Sciences
| | - Sahar Yarahmadi
- Department of Biochemistry and Nutrition, School of Medicine Iran University of Medical Sciences
| | - Soudabeh Fallah
- Department of Biochemistry and Nutrition, School of Medicine Iran University of Medical Sciences
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13
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Hematopoietic Progenitors and the Bone Marrow Niche Shape the Inflammatory Response and Contribute to Chronic Disease. Int J Mol Sci 2022; 23:ijms23042234. [PMID: 35216355 PMCID: PMC8879433 DOI: 10.3390/ijms23042234] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 02/14/2022] [Accepted: 02/15/2022] [Indexed: 11/17/2022] Open
Abstract
It is now well understood that the bone marrow (BM) compartment can sense systemic inflammatory signals and adapt through increased proliferation and lineage skewing. These coordinated and dynamic alterations in responding hematopoietic stem and progenitor cells (HSPCs), as well as in cells of the bone marrow niche, are increasingly viewed as key contributors to the inflammatory response. Growth factors, cytokines, metabolites, microbial products, and other signals can cause dysregulation across the entire hematopoietic hierarchy, leading to lineage-skewing and even long-term functional adaptations in bone marrow progenitor cells. These alterations may play a central role in the chronicity of disease as well as the links between many common chronic disorders. The possible existence of a form of “memory” in bone marrow progenitor cells is thought to contribute to innate immune responses via the generation of trained immunity (also called innate immune memory). These findings highlight how hematopoietic progenitors dynamically adapt to meet the demand for innate immune cells and how this adaptive response may be beneficial or detrimental depending on the context. In this review, we will discuss the role of bone marrow progenitor cells and their microenvironment in shaping the scope and scale of the immune response in health and disease.
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14
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Eckel RH, Bornfeldt KE, Goldberg IJ. Cardiovascular disease in diabetes, beyond glucose. Cell Metab 2021; 33:1519-1545. [PMID: 34289375 PMCID: PMC8411849 DOI: 10.1016/j.cmet.2021.07.001] [Citation(s) in RCA: 96] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 05/21/2021] [Accepted: 07/01/2021] [Indexed: 02/06/2023]
Abstract
Despite the decades-old knowledge that diabetes mellitus is a major risk factor for cardiovascular disease, the reasons for this association are only partially understood. While this association is true for both type 1 and type 2 diabetes, different pathophysiological processes may be responsible. Lipids and other risk factors are indeed important, whereas the role of glucose is less clear. This lack of clarity stems from clinical trials that do not unambiguously show that intensive glycemic control reduces cardiovascular events. Animal models have provided mechanisms that link diabetes to increased atherosclerosis, and evidence consistent with the importance of factors beyond hyperglycemia has emerged. We review clinical, pathological, and animal studies exploring the pathogenesis of atherosclerosis in humans living with diabetes and in mouse models of diabetes. An increased effort to identify risk factors beyond glucose is now needed to prevent the increased cardiovascular disease risk associated with diabetes.
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Affiliation(s)
- Robert H Eckel
- Divisions of Endocrinology, Metabolism and Diabetes, and Cardiology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, USA.
| | - Karin E Bornfeldt
- Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, and Department of Laboratory Medicine and Pathology, University of Washington Medicine Diabetes Institute, University of Washington, Seattle, WA, USA
| | - Ira J Goldberg
- Division of Endocrinology, Diabetes and Metabolism, NYU Grossman School of Medicine, New York, NY, USA
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15
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Trakaki A, Marsche G. Current Understanding of the Immunomodulatory Activities of High-Density Lipoproteins. Biomedicines 2021; 9:biomedicines9060587. [PMID: 34064071 PMCID: PMC8224331 DOI: 10.3390/biomedicines9060587] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 05/17/2021] [Accepted: 05/19/2021] [Indexed: 02/06/2023] Open
Abstract
Lipoproteins interact with immune cells, macrophages and endothelial cells - key players of the innate and adaptive immune system. High-density lipoprotein (HDL) particles seem to have evolved as part of the innate immune system since certain HDL subspecies contain combinations of apolipoproteins with immune regulatory functions. HDL is enriched in anti-inflammatory lipids, such as sphingosine-1-phosphate and certain saturated lysophospholipids. HDL reduces inflammation and protects against infection by modulating immune cell function, vasodilation and endothelial barrier function. HDL suppresses immune cell activation at least in part by modulating the cholesterol content in cholesterol/sphingolipid-rich membrane domains (lipid rafts), which play a critical role in the compartmentalization of signaling pathways. Acute infections, inflammation or autoimmune diseases lower HDL cholesterol levels and significantly alter HDL metabolism, composition and function. Such alterations could have a major impact on disease progression and may affect the risk for infections and cardiovascular disease. This review article aims to provide a comprehensive overview of the immune cell modulatory activities of HDL. We focus on newly discovered activities of HDL-associated apolipoproteins, enzymes, lipids, and HDL mimetic peptides.
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16
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Mitrofanova A, Burke G, Merscher S, Fornoni A. New insights into renal lipid dysmetabolism in diabetic kidney disease. World J Diabetes 2021; 12:524-540. [PMID: 33995842 PMCID: PMC8107981 DOI: 10.4239/wjd.v12.i5.524] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/31/2021] [Accepted: 04/26/2021] [Indexed: 02/06/2023] Open
Abstract
Lipid dysmetabolism is one of the main features of diabetes mellitus and manifests by dyslipidemia as well as the ectopic accumulation of lipids in various tissues and organs, including the kidney. Research suggests that impaired cholesterol metabolism, increased lipid uptake or synthesis, increased fatty acid oxidation, lipid droplet accumulation and an imbalance in biologically active sphingolipids (such as ceramide, ceramide-1-phosphate and sphingosine-1-phosphate) contribute to the development of diabetic kidney disease (DKD). Currently, the literature suggests that both quality and quantity of lipids are associated with DKD and contribute to increased reactive oxygen species production, oxidative stress, inflammation, or cell death. Therefore, control of renal lipid dysmetabolism is a very important therapeutic goal, which needs to be archived. This article will review some of the recent advances leading to a better understanding of the mechanisms of dyslipidemia and the role of particular lipids and sphingolipids in DKD.
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Affiliation(s)
- Alla Mitrofanova
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, FL 33136, United States
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL 33136, United States
- Department of Surgery, University of Miami, Miller School of Medicine, Miami, FL 33136, United States
| | - George Burke
- Department of Surgery, University of Miami, Miller School of Medicine, Miami, FL 33136, United States
- Diabetes Research Institute, University of Miami, Miller School of Medicine, Miami, FL 33136, United States
| | - Sandra Merscher
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, FL 33136, United States
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL 33136, United States
| | - Alessia Fornoni
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, FL 33136, United States
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL 33136, United States
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17
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The Susceptibility to Diet-Induced Atherosclerosis Is Exacerbated with Aging in C57B1/6 Mice. Biomedicines 2021; 9:biomedicines9050487. [PMID: 33946646 PMCID: PMC8146644 DOI: 10.3390/biomedicines9050487] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 04/14/2021] [Accepted: 04/21/2021] [Indexed: 12/27/2022] Open
Abstract
The anti-atherogenic activity of HDL is mainly due to their capacity to mediate reverse cholesterol transport (RCT). However, it is not clear to what extent this activity is affected by aging or pro-atherogenic conditions. Three and 24-month-old C57Bl/6 mice were fed an atherogenic diet (high fat, high cholesterol) for 12 weeks. The aged mice displayed a significant reduction in the capacity of HDL to mediate RCT (29.03%, p < 0.0006). Interestingly, the atherogenic diet significantly stimulated the RCT process in both young and aged mice (241% and 201%, respectively, p < 0.01). However, despite this, significant amounts of cholesterol accumulated in the aortas of mice fed an atherogenic diet as compared to regular chow. The accumulation of cholesterol was more marked in the aortas of aged mice (110% increase, p < 0.002). ABCA1 and ABCG1 protein expression on macrophages decreased significantly (52 to 37% reduction, p < 0.002), whereas their expression on hepatic cells increased significantly (up to 590% for ABCA1 and 116% for ABCG1, p < 0.002). On the other hand, SR-BI protein expression on hepatic cells decreased significantly (42.85%, p < 0.0001). ABCG5, ABCG8, and CYP7a protein expression on hepatic cells was also higher in mice fed an atherogenic diet. The increase was age-dependent for both ABCG5 and ABCG8. Our results suggest that the susceptibility to diet-induced atherosclerosis is exacerbated with aging and is a consequence of the dysregulation of the expression levels of membrane cholesterol transporters.
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18
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Ben Aissa M, Lewandowski CT, Ratia KM, Lee SH, Layden BT, LaDu MJ, Thatcher GRJ. Discovery of Nonlipogenic ABCA1 Inducing Compounds with Potential in Alzheimer's Disease and Type 2 Diabetes. ACS Pharmacol Transl Sci 2021; 4:143-154. [PMID: 33615168 PMCID: PMC7887740 DOI: 10.1021/acsptsci.0c00149] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Indexed: 02/07/2023]
Abstract
Selective liver X receptor (LXR) agonists have been extensively pursued as therapeutics for Alzheimer's disease and related dementia (ADRD) and, for comorbidities such as type 2 diabetes (T2D) and cerebrovascular disease (CVD), disorders with underlying impaired insulin signaling, glucose metabolism, and cholesterol mobilization. The failure of the LXR-focused approach led us to pursue a novel strategy to discover nonlipogenic ATP-binding cassette transporter A1 (ABCA1) inducers (NLAIs): screening for ABCA1-luciferase activation in astrocytoma cells and counterscreening against lipogenic gene upregulation in hepatocarcinoma cells. Beneficial effects of LXRβ agonists mediated by ABCA1 include the following: control of cholesterol and phospholipid efflux to lipid-poor apolipoproteins forming beneficial peripheral HDL and HDL-like particles in the brain and attenuation of inflammation. While rare, ABCA1 variants reduce plasma HDL and correlate with an increased risk of ADRD and CVD. In secondary assays, NLAI hits enhanced cholesterol mobilization and positively impacted in vitro biomarkers associated with insulin signaling, inflammatory response, and biogenic properties. In vivo target engagement was demonstrated after oral administration of NLAIs in (i) mice fed a high-fat diet, a model for obesity-linked T2D, (ii) mice administered LPS, and (iii) mice with accelerated oxidative stress. The lack of adverse effects on lipogenesis and positive effects on multiple biomarkers associated with T2D and ADRD supports this novel phenotypic approach to NLAIs as a platform for T2D and ADRD drug discovery.
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Affiliation(s)
- Manel Ben Aissa
- Department
of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago (UIC), Chicago, Illinois 60612, United States
- UICentre
(Drug Discovery @ UIC), University of Illinois
at Chicago (UIC), Chicago, Illinois 60612, United States
| | - Cutler T. Lewandowski
- Department
of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago (UIC), Chicago, Illinois 60612, United States
| | - Kiira M. Ratia
- HTS
Screening Facility, Research Resources Center, University of Illinois at Chicago (UIC), Chicago, Illinois 60612, United States
| | - Sue H. Lee
- Department
of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago (UIC), Chicago, Illinois 60612, United States
| | - Brian T. Layden
- Department
of Medicine, University of Illinois at Chicago
(UIC), Chicago, Illinois 60612, United States
| | - Mary Jo LaDu
- Department
of Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago (UIC), Chicago, Illinois 60612, United States
| | - Gregory R. J. Thatcher
- Department
of Pharmacology & Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona 85721, United States
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19
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Nakamichi R, Hayashi K, Itoh H. Effects of High Glucose and Lipotoxicity on Diabetic Podocytes. Nutrients 2021; 13:nu13010241. [PMID: 33467659 PMCID: PMC7830342 DOI: 10.3390/nu13010241] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 12/11/2020] [Accepted: 01/11/2021] [Indexed: 01/19/2023] Open
Abstract
Glomerular podocytes are highly differentiated cells that cover glomerular capillaries from the outside and have a characteristic morphology with numerous foot processes. The formation of slit membranes between the foot processes serves as a final filtration barrier for urine filtration from the blood. Podocyte damage causes disruption of the slit membrane, subsequent proteinuria and finally glomerulosclerosis, which is a common pathway in various types of chronic kidney disease (CKD). In recent years, there has been an increase in diabetes, due to rapid lifestyle changes, which is the main cause of CKD. Therefore, understanding the effect of diabetic status on podocytes is of great importance to establish a strategy for preventing CKD progression. In this review, we summarize altered glucose and lipid metabolism in diabetic podocytes and also discuss the reversibility of the changes in podocyte phenotype.
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Affiliation(s)
| | - Kaori Hayashi
- Correspondence: ; Tel.: +81-3-5363-3796; Fax: +81-3-3359-2745
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20
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Exosomes derived from bone marrow mesenchymal stem cells harvested from type two diabetes rats promotes neurorestorative effects after stroke in type two diabetes rats. Exp Neurol 2020; 334:113456. [PMID: 32889008 DOI: 10.1016/j.expneurol.2020.113456] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 07/08/2020] [Accepted: 08/30/2020] [Indexed: 12/26/2022]
Abstract
BACKGROUND AND PURPOSE Diabetes elevates the risk of stroke, promotes inflammation, and exacerbates vascular and white matter damage post stroke, thereby hindering long term functional recovery. Here, we investigated the neurorestorative effects and the underlying therapeutic mechanisms of treatment of stroke in type 2 diabetic rats (T2DM) using exosomes harvested from bone marrow stromal cells obtained from T2DM rats (T2DM-MSC-Exo). METHODS T2DM was induced in adult male Wistar rats using a combination of high fat diet and Streptozotocin. Rats were subjected to transient 2 h middle cerebral artery occlusion (MCAo) and 3 days later randomized to one of the following treatment groups: 1) phosphate-buffered-saline (PBS, i.v), 2) T2DM-MSC-Exo, (3 × 1011, i.v), 3) T2DM-MSC-Exo with miR-9 over expression (miR9+/+-T2DM-MSC-Exo, 3 × 1011, i.v) or 4) MSC-Exo derived from normoglycemic rats (Nor-MSC-Exo) (3 × 1011, i.v). T2DM sham control group is included as reference. Rats were sacrificed 28 days after MCAo. RESULTS T2DM-MSC-Exo treatment does not alter blood glucose, lipid levels, or lesion volume, but significantly improves neurological function and attenuates post-stroke weight loss compared to PBS treated as well as Nor-MSC-Exo treated T2DM-stroke rats. Compared to PBS treatment, T2DM-MSC-Exo treatment of T2DM-stroke rats significantly 1) increases tight junction protein ZO-1 and improves blood brain barrier (BBB) integrity; 2) promotes white matter remodeling indicated by increased axon and myelin density, and increases oligodendrocytes and oligodendrocyte progenitor cell numbers in the ischemic border zone as well as increases primary cortical neuronal axonal outgrowth; 3) decreases activated microglia, M1 macrophages, and inflammatory factors MMP-9 (matrix mettaloproteinase-9) and MCP-1 (monocyte chemoattractant protein-1) expression in the ischemic brain; and 4) decreases miR-9 expression in serum, and increases miR-9 target ABCA1 (ATP-binding cassette transporter 1) and IGFR1 (Insulin-like growth factor 1 receptor) expression in the brain. MiR9+/+-T2DM-MSC-Exo treatment significantly increases serum miR-9 expression compared to PBS treated and T2DM-MSC-Exo treated T2DM stroke rats. Treatment of T2DM stroke with miR9+/+-T2DM-MSC-Exo fails to improve functional outcome and attenuates T2DM-MSC-Exo treatment induced white matter remodeling and anti-inflammatory effects in T2DM stroke rats. CONCLUSIONS T2DM-MSC-Exo treatment for stroke in T2DM rats promotes neurorestorative effects and improves functional outcome. Down regulation of miR-9 expression and increasing its target ABCA1 pathway may contribute partially to T2DM-MSC-Exo treatment induced white matter remodeling and anti-inflammatory responses.
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21
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Mitrofanova A, Drexler Y, Merscher S, Fornoni A. Role of Sphingolipid Signaling in Glomerular Diseases: Focus on DKD and FSGS. JOURNAL OF CELLULAR SIGNALING 2020; 1:56-69. [PMID: 32914148 PMCID: PMC7480905 DOI: 10.33696/signaling.1.013] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Sphingolipids are well-recognized as major players in the pathogenesis of many human diseases, including chronic kidney disease. The kidney is a very sensitive organ to alterations in sphingolipid metabolism. The critical issues to be addressed in this review relate to the role of sphingolipids and enzymes involved in sphingolipid metabolism in the pathogenesis of glomerular diseases with a special focus on podocytes, a key cellular component of the glomerular filtration barrier. Among several sphingolipids, we will highlight the role of ceramide, sphingosine, sphingosine-1-phosphate and ceramide-1-phosphate. Additionally, we will summarize the current knowledge with regard to the use of sphingolipids as therapeutic agents for the treatment of podocyte injury in kidney disease.
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Affiliation(s)
- Alla Mitrofanova
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida, USA
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, Florida, USA
- Department of Surgery, University of Miami, Miller School of Medicine, Miami, Florida, USA
| | - Yelena Drexler
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida, USA
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, Florida, USA
| | - Sandra Merscher
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida, USA
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, Florida, USA
| | - Alessia Fornoni
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida, USA
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, Florida, USA
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22
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Inhibition of miR-17~92 Cluster Ameliorates High Glucose-Induced Podocyte Damage. Mediators Inflamm 2020; 2020:6126490. [PMID: 32774146 PMCID: PMC7391105 DOI: 10.1155/2020/6126490] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 05/13/2020] [Accepted: 06/13/2020] [Indexed: 12/13/2022] Open
Abstract
The loss and damage of podocytes is an early feature of diabetic nephropathy (DN). The miR-17∼92 cluster was dysregulated in diabetic and polycystic kidney disease patients, but its role in DN is unclear. Hence, an in vitro study on the high glucose- (HG-) treated mouse podocytes (MPC5) was designed to elucidate the effect of miR-17∼92 cluster downregulation on cell viability, apoptosis, inflammation, fibrosis, and podocyte function. The results suggested that the miR-17∼92 cluster members miR-17-5p, miR-18a, miR-19a, miR-19b, miR-20a, and miR-92a were upregulated in the renal biopsy tissue of DN patients and HG-treated MPC5. The downregulation of the miR-17∼92 cluster effectively suppressed the cell apoptosis, inflammation, fibrosis, and podocyte dysfunction in HG-stimulated MPC5 cells. The bioinformatics analysis and rescue experiments showed that ABCA1 (ATP-binding cassette transporter A1) is an effector of the miR-17~92 cluster. Silence of ABCA1 inhibited the protective effect of the miR-17∼92 cluster downregulation on podocyte damage. In summary, this research indicated that the downregulation of the miR-17∼92 cluster ameliorates HG-induced podocyte damage via targeting ABCA1.
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23
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Srivastava N, Cefalu AB, Averna M, Srivastava RAK. Rapid degradation of ABCA1 protein following cAMP withdrawal and treatment with PKA inhibitor suggests ABCA1 is a short-lived protein primarily regulated at the transcriptional level. J Diabetes Metab Disord 2020; 19:363-371. [PMID: 32550187 DOI: 10.1007/s40200-020-00517-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Accepted: 03/12/2020] [Indexed: 01/08/2023]
Abstract
Objectives ATP-binding cassette transporter A1 (ABCA1) is a key player in the reverse cholesterol transport (RCT) and HDL biogenesis. Since RCT is compromised as a result of ABCA1 dysfunction in diabetic state, the objective of this study was to investigate the regulation of ABCA1 in a stably transfected 293 cells expressing ABCA1 under the control of cAMP response element. Methods To delineate transcriptional and posttranscriptional regulation of ABCA1, 293 cells were stably transfected with the full length ABCA1 cDNA under the control of CMV promoter harboring cAMP response element. cAMP-mediated regulation of ABCA1 and cholesterol efflux were studied in the presence of 8-Br-cAMP and after withdrawal of 8-Br-cAMP. The mechanism of cAMP-mediated transcriptional induction of the ABCA1 gene was studied in protein kinase A (PKA) inhibitors-treated cells. Results The transfected 293 cells expressed high levels of ABCA1, while non-transfected wild-type 293 cells showed very low levels of ABCA1. Treatments of transfected cells with 8-Br-cAMP increased ABCA1 protein by 10-fold and mRNA by 20-fold. Cholesterol efflux also increased in parallel. Withdrawal of 8-Br-cAMP caused time-dependent rapid diminution of ABCA1 protein and mRNA, suggesting ABCA1 regulation at the transcriptional level. Treatment with PKA inhibitors abolished the cAMP-mediated induction of the ABCA1 mRNA and protein, resulting dampening of ABCA1-dependent cholesterol efflux. Conclusions These results demonstrate that transfected cell line mimics cAMP response similar to normal cells with natural ABCA1 promoter and suggest that ABCA1 is a short-lived protein primarily regulated at the transcriptional level to maintain cellular cholesterol homeostasis.
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Abdel-Megeed RM, El Newary SA, Kadry MO, Ghanem HZ, El-Shesheny RA, Said-Al Ahl HAH, Abdel-Hamid AHZ. Hyssopus officinalis exerts hypoglycemic effects on streptozotocin-induced diabetic rats via modulating GSK-3β, C-fos, NF-κB, ABCA1 and ABGA1 gene expression. J Diabetes Metab Disord 2020; 19:483-491. [PMID: 32550200 DOI: 10.1007/s40200-020-00535-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 04/22/2020] [Accepted: 04/28/2020] [Indexed: 12/23/2022]
Abstract
Objectives Type 2 diabetes mellitus (DMT2) is contributed to dual interactions between environmental factors and certain genetic factors. This impressed a great need for novel treatment strategy. Nevertheless, Hyssopus officinalis (H. officinalis) as a terrestrial herb is considered to be an important source of natural antioxidants, it could be assessed as an anti-hyperglycemic agent. Methods In the current study, HPLC identified the active constitutes of H. officinalis, including total polyphenols, and flavonoids. Type 2 diabetes mellitus was induced in male Wistar albino rats via a single ip dose of streptozotocin (STZ) (35 mg/kg BW). One week post diabetes induction, rats were administrated H. officinalis (500 mg/ kg BW) orally for one month. Molecular analysis was assessed to investigate the efficiency of H. officinalis on modulating ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1) genes, in addition to apoptotic biomarkers, glycogen synthase kinase-3β (GSK-3β) and cellular oncogene-fos (C-fos) genes. Furthermore, inflammatory biomarkers, nuclear factor kappa-B (NF-κB) and tumor necrosis factor-α (TNF-α) gene expression were also assessed. Results H. officinalis alcoholic extract declared the presence of polyphenols as gallic acid and flavonoids as quercetin in addition to many active constituents. Apigenin-7-glucoside and Chlorgenic acid were the most common constituents in the extract. RT-PCR results declared a significant up-regulation in mRNA gene expression of ABCA1 and ABCG1 upon H. officinalis treatment. Meanwhile, C-fos gene expression recorded a slight down-regulation. Gene expression of apoptotic biomarker GSK-3β demonstrated a significant down regulation as well as inflammatory biomarkers NF-κB and TNF-α. Conclusion From the data recorded, it could be concluded that H. officinalis exerts a great hypoglycemic potential via modulating C-fos, GSK-3β, NF-κB, TNF-α, ABCA1 and ABCG1 gene expression and signaling pathways and could be considered as an effective candidate for DMT2 treatment.
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Affiliation(s)
- Rehab M Abdel-Megeed
- Therapeutic Chemistry Department, Pharmaceutical and Drug Industries Division, National Research Center, El Buhouth St., Dokki, Cairo, 12622 Egypt
| | - Samah A El Newary
- Medicinal and Aromatic Plants Researches Department, Pharmaceutical and Drug Industries Division, National Research Centre, El Buhouth St., Dokki, Cairo, Egypt
| | - Mai O Kadry
- Therapeutic Chemistry Department, Pharmaceutical and Drug Industries Division, National Research Center, El Buhouth St., Dokki, Cairo, 12622 Egypt
| | - Hassan Z Ghanem
- Therapeutic Chemistry Department, Pharmaceutical and Drug Industries Division, National Research Center, El Buhouth St., Dokki, Cairo, 12622 Egypt
| | - Rabeh A El-Shesheny
- Center of Scientific Excellence for Influenza Viruses, Environmental Research Division, National Research Center, El Buhouth St., Dokki, Cairo, Egypt
| | - Hussein A H Said-Al Ahl
- Medicinal and Aromatic Plants Researches Department, Pharmaceutical and Drug Industries Division, National Research Centre, El Buhouth St., Dokki, Cairo, Egypt
| | - Abdel-Hamid Z Abdel-Hamid
- Therapeutic Chemistry Department, Pharmaceutical and Drug Industries Division, National Research Center, El Buhouth St., Dokki, Cairo, 12622 Egypt
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25
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Castaño D, Rattanasopa C, Monteiro-Cardoso VF, Corlianò M, Liu Y, Zhong S, Rusu M, Liehn EA, Singaraja RR. Lipid efflux mechanisms, relation to disease and potential therapeutic aspects. Adv Drug Deliv Rev 2020; 159:54-93. [PMID: 32423566 DOI: 10.1016/j.addr.2020.04.013] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 04/29/2020] [Accepted: 04/30/2020] [Indexed: 02/06/2023]
Abstract
Lipids are hydrophobic and amphiphilic molecules involved in diverse functions such as membrane structure, energy metabolism, immunity, and signaling. However, altered intra-cellular lipid levels or composition can lead to metabolic and inflammatory dysfunction, as well as lipotoxicity. Thus, intra-cellular lipid homeostasis is tightly regulated by multiple mechanisms. Since most peripheral cells do not catabolize cholesterol, efflux (extra-cellular transport) of cholesterol is vital for lipid homeostasis. Defective efflux contributes to atherosclerotic plaque development, impaired β-cell insulin secretion, and neuropathology. Of these, defective lipid efflux in macrophages in the arterial walls leading to foam cell and atherosclerotic plaque formation has been the most well studied, likely because a leading global cause of death is cardiovascular disease. Circulating high density lipoprotein particles play critical roles as acceptors of effluxed cellular lipids, suggesting their importance in disease etiology. We review here mechanisms and pathways that modulate lipid efflux, the role of lipid efflux in disease etiology, and therapeutic options aimed at modulating this critical process.
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Opazo-Ríos L, Mas S, Marín-Royo G, Mezzano S, Gómez-Guerrero C, Moreno JA, Egido J. Lipotoxicity and Diabetic Nephropathy: Novel Mechanistic Insights and Therapeutic Opportunities. Int J Mol Sci 2020; 21:E2632. [PMID: 32290082 PMCID: PMC7177360 DOI: 10.3390/ijms21072632] [Citation(s) in RCA: 201] [Impact Index Per Article: 40.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 04/07/2020] [Accepted: 04/08/2020] [Indexed: 02/06/2023] Open
Abstract
Lipotoxicity is characterized by the ectopic accumulation of lipids in organs different from adipose tissue. Lipotoxicity is mainly associated with dysfunctional signaling and insulin resistance response in non-adipose tissue such as myocardium, pancreas, skeletal muscle, liver, and kidney. Serum lipid abnormalities and renal ectopic lipid accumulation have been associated with the development of kidney diseases, in particular diabetic nephropathy. Chronic hyperinsulinemia, often seen in type 2 diabetes, plays a crucial role in blood and liver lipid metabolism abnormalities, thus resulting in increased non-esterified fatty acids (NEFA). Excessive lipid accumulation alters cellular homeostasis and activates lipogenic and glycogenic cell-signaling pathways. Recent evidences indicate that both quantity and quality of lipids are involved in renal damage associated to lipotoxicity by activating inflammation, oxidative stress, mitochondrial dysfunction, and cell-death. The pathological effects of lipotoxicity have been observed in renal cells, thus promoting podocyte injury, tubular damage, mesangial proliferation, endothelial activation, and formation of macrophage-derived foam cells. Therefore, this review examines the recent preclinical and clinical research about the potentially harmful effects of lipids in the kidney, metabolic markers associated with these mechanisms, major signaling pathways affected, the causes of excessive lipid accumulation, and the types of lipids involved, as well as offers a comprehensive update of therapeutic strategies targeting lipotoxicity.
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Affiliation(s)
- Lucas Opazo-Ríos
- Renal, Vascular and Diabetes Research Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28040 Madrid, Spain; (L.O.-R.); (G.M.-R.); (C.G.-G.); (J.E.)
| | - Sebastián Mas
- Renal, Vascular and Diabetes Research Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28040 Madrid, Spain; (L.O.-R.); (G.M.-R.); (C.G.-G.); (J.E.)
| | - Gema Marín-Royo
- Renal, Vascular and Diabetes Research Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28040 Madrid, Spain; (L.O.-R.); (G.M.-R.); (C.G.-G.); (J.E.)
| | - Sergio Mezzano
- Laboratorio de Nefrología, Facultad de Medicina, Universidad Austral de Chile, 5090000 Valdivia, Chile;
| | - Carmen Gómez-Guerrero
- Renal, Vascular and Diabetes Research Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28040 Madrid, Spain; (L.O.-R.); (G.M.-R.); (C.G.-G.); (J.E.)
| | - Juan Antonio Moreno
- Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14004 Cordoba, Spain
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), University of Cordoba, 14004 Cordoba, Spain
- Hospital Universitario Reina Sofía, 14004 Cordoba, Spain
| | - Jesús Egido
- Renal, Vascular and Diabetes Research Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28040 Madrid, Spain; (L.O.-R.); (G.M.-R.); (C.G.-G.); (J.E.)
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27
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McPherson KC, Shields CA, Poudel B, Johnson AC, Taylor L, Stubbs C, Nichols A, Cornelius DC, Garrett MR, Williams JM. Altered renal hemodynamics is associated with glomerular lipid accumulation in obese Dahl salt-sensitive leptin receptor mutant rats. Am J Physiol Renal Physiol 2020; 318:F911-F921. [PMID: 32068459 DOI: 10.1152/ajprenal.00438.2019] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
The present study examined whether development of renal injury in the nondiabetic obese Dahl salt-sensitive leptin receptor mutant (SSLepRmutant) strain is associated with elevations in glomerular filtration rate and renal lipid accumulation. Baseline mean arterial pressure at 6 wk of age was similar between Dahl salt-sensitive wild-type (SSWT) and SSLepRmutant rats. However, by 18 wk of age, the SSLepRmutant strain developed hypertension, while the elevation in mean arterial pressure was not as severe in SSWT rats (192 ± 4 and 149 ± 6 mmHg, respectively). At baseline, proteinuria was fourfold higher in SSLepRmutant than SSWT rats and remained elevated throughout the study. The early development of progressive proteinuria was associated with renal hyperfiltration followed by a decline in renal function over the course of study in the SSLepRmutant compared with SSWT rats. Kidneys from the SSLepRmutant strain displayed more glomerulosclerosis and glomerular lipid accumulation than SSWT rats. Glomeruli were isolated from the renal cortex of both strains at 6 and 18 wk of age, and RNA sequencing was performed to identify genes and pathways driving glomerular injury. We observed significant increases in expression of the influx lipid transporters, chemokine (C-X-C motif) ligand 16 (Cxcl16) and scavenger receptor and fatty acid translocase (Cd36), respectively, and a significant decrease in expression of the efflux lipid transporter, ATP-binding cassette subfamily A member 2 (Abca2; cholesterol efflux regulatory protein 2), in SSLepRmutant compared with SSWT rats at 6 and 18 wk of age, which were validated by RT-PCR analysis. These data suggest an association between glomerular hyperfiltration and glomerular lipid accumulation during the early development of proteinuria associated with obesity.
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Affiliation(s)
- Kasi C McPherson
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi
| | - Corbin A Shields
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi
| | - Bibek Poudel
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi
| | - Ashley C Johnson
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi
| | - Lateia Taylor
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi
| | - Cassandra Stubbs
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi
| | - Alyssa Nichols
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi
| | - Denise C Cornelius
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi.,Department of Emergency Medicine, University of Mississippi Medical Center, Jackson, Mississippi
| | - Michael R Garrett
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi
| | - Jan M Williams
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi
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Kanter JE, Hsu CC, Bornfeldt KE. Monocytes and Macrophages as Protagonists in Vascular Complications of Diabetes. Front Cardiovasc Med 2020; 7:10. [PMID: 32118048 PMCID: PMC7033616 DOI: 10.3389/fcvm.2020.00010] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Accepted: 01/27/2020] [Indexed: 12/16/2022] Open
Abstract
With the increasing prevalence of diabetes worldwide, vascular complications of diabetes are also on the rise. Diabetes results in an increased risk of macrovascular complications, with atherosclerotic cardiovascular disease (CVD) being the leading cause of death in adults with diabetes. The exact mechanisms for how diabetes promotes CVD risk are still unclear, although it is evident that monocytes and macrophages are key players in all stages of atherosclerosis both in the absence and presence of diabetes, and that phenotypes of these cells are altered by the diabetic environment. Evidence suggests that at least five pro-atherogenic mechanisms involving monocytes and macrophages contribute to the accelerated atherosclerotic lesion progression and hampered lesion regression associated with diabetes. These changes include (1) increased monocyte recruitment to lesions; (2) increased inflammatory activation; (3) altered macrophage lipid accumulation and metabolism; (4) increased macrophage cell death; and (5) reduced efferocytosis. Monocyte and macrophage phenotypes and mechanisms have been revealed mostly by different animal models of diabetes. The roles of specific changes in monocytes and macrophages in humans with diabetes remain largely unknown. There is an ongoing debate on whether the changes in monocytes and macrophages are caused by altered glucose levels, insulin deficiency or insulin resistance, lipid abnormalities, or combinations of these factors. Current research in humans and mouse models suggests that reduced clearance of triglyceride-rich lipoproteins and their remnants is one important mechanism whereby diabetes adversely affects macrophages and promotes atherosclerosis and CVD risk. Although monocytes and macrophages readily respond to the diabetic environment and can be seen as protagonists in diabetes-accelerated atherosclerosis, they are likely not instigators of the increased CVD risk.
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Affiliation(s)
- Jenny E Kanter
- Department of Medicine, University of Washington Medicine Diabetes Institute, University of Washington School of Medicine, Seattle, WA, United States
| | - Cheng-Chieh Hsu
- Department of Medicine, University of Washington Medicine Diabetes Institute, University of Washington School of Medicine, Seattle, WA, United States
| | - Karin E Bornfeldt
- Department of Medicine, University of Washington Medicine Diabetes Institute, University of Washington School of Medicine, Seattle, WA, United States.,Department of Pathology, University of Washington Medicine Diabetes Institute, University of Washington School of Medicine, Seattle, WA, United States
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Matsuda J, Takahashi A, Takabatake Y, Sakai S, Minami S, Yamamoto T, Fujimura R, Namba-Hamano T, Yonishi H, Nakamura J, Kimura T, Kaimori JY, Matsui I, Takahashi M, Nakao M, Izumi Y, Bamba T, Matsusaka T, Niimura F, Yanagita M, Yoshimori T, Isaka Y. Metabolic effects of RUBCN/Rubicon deficiency in kidney proximal tubular epithelial cells. Autophagy 2020; 16:1889-1904. [PMID: 31944172 DOI: 10.1080/15548627.2020.1712107] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Macroautophagy/autophagy is a lysosomal degradation system which plays a protective role against kidney injury. RUBCN/Rubicon (RUN domain and cysteine-rich domain containing, Beclin 1-interacting protein) inhibits the fusion of autophagosomes and lysosomes. However, its physiological role in kidney proximal tubular epithelial cells (PTECs) remains uncertain. In the current study, we analyzed the phenotype of newly generated PTEC-specific rubcn-deficient (KO) mice. Additionally, we investigated the role of RUBCN in lipid metabolism using isolated rubcn-deficient PTECs. Although KO mice exhibited sustained high autophagic flux in PTECs, they were not protected from acute ischemic kidney injury. Unexpectedly, KO mice exhibited hallmark features of metabolic syndrome accompanied by expanded lysosomes containing multi-layered phospholipids in PTECs. RUBCN deficiency in cultured PTECs promoted the mobilization of phospholipids from cellular membranes to lysosomes via enhanced autophagy. Treatment of KO PTECs with oleic acid accelerated fatty acids transfer to mitochondria. Furthermore, KO PTECs promoted massive triglyceride accumulation in hepatocytes (BNL-CL2 cells) co-cultured in transwell, suggesting accelerated fatty acids efflux from the PTECs contributes to the metabolic syndrome in KO mice. This study shows that sustained high autophagic flux by RUBCN deficiency in PTECs leads to metabolic syndrome concomitantly with an accelerated mobilization of phospholipids from cellular membranes to lysosomes. Abbreviations: ABC: ATP binding cassette; ACADM: acyl-CoA dehydrogenase medium chain; ACTB: actin, beta; ATG: autophagy related; AUC: area under the curve; Baf: bafilomycin A1; BAT: brown adipose tissue; BODIPY: boron-dipyrromethene; BSA: bovine serum albumin; BW: body weight; CAT: chloramphenicol acetyltransferase; CM: complete medium; CPT1A: carnitine palmitoyltransferase 1a, liver; CQ: chloroquine; CTRL: control; EGFP: enhanced green fluorescent protein; CTSD: cathepsin D; EAT: epididymal adipose tissue; EGFR: epidermal growth factor receptor; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; FA: fatty acid; FBS: fetal bovine serum; GTT: glucose tolerance test; HE: hematoxylin and eosin; HFD: high-fat diet; I/R: ischemia-reperfusion; ITT: insulin tolerance test; KAP: kidney androgen regulated protein; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LD: lipid droplet; LRP2: low density lipoprotein receptor related protein 2; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MAT: mesenteric adipose tissue; MS: mass spectrometry; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; NDRG1: N-myc downstream regulated 1; NDUFB5: NADH:ubiquinone oxidoreductase subunit B5; NEFA: non-esterified fatty acid; OA: oleic acid; OCT: optimal cutting temperature; ORO: Oil Red O; PAS: Periodic-acid Schiff; PFA: paraformaldehyde; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; PPARA: peroxisome proliferator activated receptor alpha; PPARGC1A: PPARG coactivator 1 alpha; PTEC: proximal tubular epithelial cell; RAB7A: RAB7A, member RAS oncogene family; RPS6: ribosomal protein S6; RPS6KB1: ribosomal protein S6 kinase B1; RT: reverse transcription; RUBCN: rubicon autophagy regulator; SAT: subcutaneous adipose tissue; SFC: supercritical fluid chromatography; SQSTM1: sequestosome 1; SREBF1: sterol regulatory element binding transcription factor 1; SV-40: simian virus-40; TFEB: transcription factor EB; TG: triglyceride; TS: tissue specific; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling; UN: urea nitrogen; UQCRB: ubiquinol-cytochrome c reductase binding protein; UVRAG: UV radiation resistance associated; VPS: vacuolar protein sorting; WAT: white adipose tissue.
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Affiliation(s)
- Jun Matsuda
- Department of Nephrology, Osaka University Graduate School of Medicine , Osaka, Japan
| | - Atsushi Takahashi
- Department of Nephrology, Osaka University Graduate School of Medicine , Osaka, Japan
| | - Yoshitsugu Takabatake
- Department of Nephrology, Osaka University Graduate School of Medicine , Osaka, Japan
| | - Shinsuke Sakai
- Department of Nephrology, Osaka University Graduate School of Medicine , Osaka, Japan
| | - Satoshi Minami
- Department of Nephrology, Osaka University Graduate School of Medicine , Osaka, Japan
| | - Takeshi Yamamoto
- Department of Nephrology, Osaka University Graduate School of Medicine , Osaka, Japan
| | - Ryuta Fujimura
- Department of Nephrology, Osaka University Graduate School of Medicine , Osaka, Japan
| | - Tomoko Namba-Hamano
- Department of Nephrology, Osaka University Graduate School of Medicine , Osaka, Japan
| | - Hiroaki Yonishi
- Department of Nephrology, Osaka University Graduate School of Medicine , Osaka, Japan
| | - Jun Nakamura
- Department of Nephrology, Osaka University Graduate School of Medicine , Osaka, Japan
| | - Tomonori Kimura
- Department of Nephrology, Osaka University Graduate School of Medicine , Osaka, Japan.,Reverse Translational Project, Center for Rare Disease Research, National Institute of Biomedical Innovation, Health and Nutrition (NIBIOHN) , Osaka, Japan
| | - Jun-Ya Kaimori
- Department of Advanced Technology for Transplantation, Osaka University Graduate School of Medicine , Osaka, Japan
| | - Isao Matsui
- Department of Nephrology, Osaka University Graduate School of Medicine , Osaka, Japan
| | - Masatomo Takahashi
- Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University , Fukuoka, Japan
| | - Motonao Nakao
- Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University , Fukuoka, Japan
| | - Yoshihiro Izumi
- Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University , Fukuoka, Japan
| | - Takeshi Bamba
- Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University , Fukuoka, Japan
| | - Taiji Matsusaka
- Institute of Medical Science and Department of Basic Sciences, Tokai University School of Medicine , Isehara, Japan
| | - Fumio Niimura
- Department of Pediatrics, Tokai University School of Medicine , Isehara, Japan
| | - Motoko Yanagita
- Department of Nephrology, Kyoto University Graduate School of Medicine , Kyoto, Japan.,Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University , Kyoto, Japan
| | - Tamotsu Yoshimori
- Department of Genetics, Osaka University Graduate School of Medicine , Osaka, Japan
| | - Yoshitaka Isaka
- Department of Nephrology, Osaka University Graduate School of Medicine , Osaka, Japan
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Abstract
PURPOSE OF REVIEW The goal of this review is to review the role that renal parenchymal lipid accumulation plays in contributing to diabetic kidney disease (DKD), specifically contributing to the mitochondrial dysfunction observed in glomerular renal cells in the context of DKD development and progression. RECENT FINDINGS Mitochondrial dysfunction has been observed in experimental and clinical DKD. Recently, Ayanga et al. demonstrate that podocyte-specific deletion of a protein involved in mitochondrial dynamics protects from DKD progression. Furthermore, our group has recently shown that ATP-binding cassette A1 (a protein involved in cholesterol and phospholipid efflux) is significantly reduced in clinical and experimental DKD and that genetic or pharmacological induction of ABCA1 is sufficient to protect from DKD. ABCA1 deficiency in podocytes leads to mitochondrial dysfunction observed with alterations of mitochondrial lipids, in particular, cardiolipin (a mitochondrial-specific phospholipid). However, through pharmacological reduction of cardiolipin peroxidation DKD progression is reverted. Lipid metabolism is significantly altered in the diabetic kidney and renders cellular components, such as the podocyte, susceptible to injury leading to worsened DKD progression. Dysfunction of the lipid metabolism pathway can also lead to mitochondrial dysfunction and mitochondrial lipid alteration. Future research aimed at targeting mitochondrial lipids content and function could prove to be beneficial for the treatment of DKD.
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Affiliation(s)
- G Michelle Ducasa
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, 1580 NW 10th Avenue, Miami, FL, USA
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - Alla Mitrofanova
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, 1580 NW 10th Avenue, Miami, FL, USA
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, FL, USA
- Department of Surgery, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - Alessia Fornoni
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, 1580 NW 10th Avenue, Miami, FL, USA.
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, FL, USA.
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Price NL, Miguel V, Ding W, Singh AK, Malik S, Rotllan N, Moshnikova A, Toczek J, Zeiss C, Sadeghi MM, Arias N, Baldán Á, Andreev OA, Rodríguez-Puyol D, Bahal R, Reshetnyak YK, Suárez Y, Fernández-Hernando C, Lamas S. Genetic deficiency or pharmacological inhibition of miR-33 protects from kidney fibrosis. JCI Insight 2019; 4:131102. [PMID: 31613798 DOI: 10.1172/jci.insight.131102] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Accepted: 10/10/2019] [Indexed: 12/18/2022] Open
Abstract
Previous work has reported the important links between cellular bioenergetics and the development of chronic kidney disease, highlighting the potential for targeting metabolic functions to regulate disease progression. More recently, it has been shown that alterations in fatty acid oxidation (FAO) can have an important impact on the progression of kidney disease. In this work, we demonstrate that loss of miR-33, an important regulator of lipid metabolism, can partially prevent the repression of FAO in fibrotic kidneys and reduce lipid accumulation. These changes were associated with a dramatic reduction in the extent of fibrosis induced in 2 mouse models of kidney disease. These effects were not related to changes in circulating leukocytes because bone marrow transplants from miR-33-deficient animals did not have a similar impact on disease progression. Most important, targeted delivery of miR-33 peptide nucleic acid inhibitors to the kidney and other acidic microenvironments was accomplished using pH low insertion peptides as a carrier. This was effective at both increasing the expression of factors involved in FAO and reducing the development of fibrosis. Together, these findings suggest that miR-33 may be an attractive therapeutic target for the treatment of chronic kidney disease.
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Affiliation(s)
- Nathan L Price
- Vascular Biology and Therapeutics Program and.,Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Verónica Miguel
- Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa," Madrid, Spain
| | - Wen Ding
- Vascular Biology and Therapeutics Program and.,Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Abhishek K Singh
- Vascular Biology and Therapeutics Program and.,Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Shipra Malik
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut, USA
| | - Noemi Rotllan
- Vascular Biology and Therapeutics Program and.,Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Anna Moshnikova
- Department of Physics, University of Rhode Island, Kingston, Rhode Island, USA
| | - Jakub Toczek
- Vascular Biology and Therapeutics Program and.,Cardiovascular Molecular Imaging Laboratory, Section of Cardiovascular Medicine, and Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut, USA.,Section of Cardiology, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, USA
| | - Caroline Zeiss
- Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Mehran M Sadeghi
- Vascular Biology and Therapeutics Program and.,Cardiovascular Molecular Imaging Laboratory, Section of Cardiovascular Medicine, and Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut, USA.,Section of Cardiology, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, USA
| | - Noemi Arias
- Edward A. Doisy Department of Biochemistry and Molecular Biology and Center for Cardiovascular Research, Saint Louis University School of Medicine, St. Louis, Missouri, USA
| | - Ángel Baldán
- Edward A. Doisy Department of Biochemistry and Molecular Biology and Center for Cardiovascular Research, Saint Louis University School of Medicine, St. Louis, Missouri, USA
| | - Oleg A Andreev
- Department of Physics, University of Rhode Island, Kingston, Rhode Island, USA
| | - Diego Rodríguez-Puyol
- Department of Medicine and Medical Specialties, Research Foundation of the University Hospital "Príncipe de Asturias," IRYCIS, Alcalá University, Alcalá de Henares, Madrid, Spain
| | - Raman Bahal
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut, USA
| | - Yana K Reshetnyak
- Department of Physics, University of Rhode Island, Kingston, Rhode Island, USA
| | - Yajaira Suárez
- Vascular Biology and Therapeutics Program and.,Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Carlos Fernández-Hernando
- Vascular Biology and Therapeutics Program and.,Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Santiago Lamas
- Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa," Madrid, Spain
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Tall AR, Westerterp M. Inflammasomes, neutrophil extracellular traps, and cholesterol. J Lipid Res 2019; 60:721-727. [PMID: 30782961 PMCID: PMC6446695 DOI: 10.1194/jlr.s091280] [Citation(s) in RCA: 98] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2018] [Revised: 02/09/2019] [Indexed: 02/07/2023] Open
Abstract
Activation of macrophage inflammasomes leads to interleukin (IL)-1β and IL-18 secretion and promotes atherosclerosis and its complications in mice and humans. However, the specific role and underlying mechanisms of the inflammasome in atherogenesis are topics of active research. Several studies in hyperlipidemic mouse models found that the NOD-like receptor protein 3 (NLRP3) inflammasome contributes to atherosclerosis, but recent work suggests that a second hit, such as defective cholesterol efflux or accumulation of oxidized mitochondrial DNA, may be required for significant inflammasome activation. Cholesterol crystal uptake or formation in lysosomes may damage membranes and activate NLRP3 inflammasomes. Alternatively, plasma or ER membrane cholesterol accumulation may condition macrophages for inflammasome activation in the presence of danger-associated molecular patterns, such as oxidized LDL. Inflammasome activation in macrophages or neutrophils leads to gasdermin-D cleavage that induces membrane pore formation, releasing IL-1β and IL-18, and eventuating in pyroptosis or neutrophil extracellular trap formation (NETosis). In humans, inflammasome activation and NETosis may contribute to atherosclerotic plaque erosion and thrombosis, especially in patients with type 2 diabetes, chronic kidney disease, or clonal hematopoiesis. Suppression of the inflammasome by activation of cholesterol efflux or by direct inhibition of inflammasome components may benefit patients with CVD and underlying susceptibility to inflammasome activation.
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Affiliation(s)
- Alan R Tall
- Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY 10032.
| | - Marit Westerterp
- Department of Pediatrics, Section Molecular Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
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O'Reilly ME, Kajani S, Ralston JC, Lenighan YM, Roche HM, McGillicuddy FC. Nutritionally Derived Metabolic Cues Typical of the Obese Microenvironment Increase Cholesterol Efflux Capacity of Adipose Tissue Macrophages. Mol Nutr Food Res 2019; 63:e1800713. [PMID: 30411491 PMCID: PMC6492173 DOI: 10.1002/mnfr.201800713] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Revised: 10/05/2018] [Indexed: 12/28/2022]
Abstract
BACKGROUND Cholesterol retention within plasma membranes of macrophages is associated with increased inflammatory signaling. Cholesterol efflux via the transporters ABCA1, ABCG1, and SR-BI to high-density lipoprotein (HDL) particles is a critical mechanism to maintain cellular cholesterol homeostasis. Little is known about the impact of the obese microenvironment on cholesterol efflux capacity (CEC) of macrophages. In this study, the CEC of obese-derived primary adipose-tissue macrophages (ATM) is evaluated and the in vivo microenvironment is modeled in vitro to determine mechanisms underlying modulated CEC. MATERIALS AND METHODS F4/80+ ATM are labeled with 3 H-cholesterol ex vivo, and CEC and ABCA1/ABCG1 protein levels are determined. Total, ABCA1-dependent, and ABCA1-independent CECs are determined in J774 macrophages polarized to M1 (LPS&IFNγ), M2 (IL-4&IL-13), or metabolic phenotypes (glucose, insulin, and palmitic acid). RESULTS Obese ATM exhibit enhanced CEC and ABCA1 and ABCG1 expression compared to lean ATM. In contrast, ABCA1-CEC is suppressed from M1 polarized macrophages compared to untreated in vitro, by activation of the JAK/STAT pathway. Incubation of macrophages in vitro in high glucose augments cAMP-induced ABCA1 protein expression and ABCA1-CEC. CONCLUSIONS These novel findings demonstrate remarkable plasticity of macrophages to respond to their environment with specific modulation of ABCA1 depending on whether classical pro-inflammatory or metabolic cues predominate.
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Affiliation(s)
- Marcella E. O'Reilly
- Nutrigenomics Research GroupSchool of Public Health Physiotherapy and Sports ScienceUniversity College DublinDublin 4Ireland
| | - Sarina Kajani
- Diabetes Complications Research CentreUCD Conway Institute and School of MedicineUniversity College DublinDublin 4Ireland
| | - Jessica C. Ralston
- Nutrigenomics Research GroupSchool of Public Health Physiotherapy and Sports ScienceUniversity College DublinDublin 4Ireland
| | - Yvonne M. Lenighan
- Nutrigenomics Research GroupSchool of Public Health Physiotherapy and Sports ScienceUniversity College DublinDublin 4Ireland
| | - Helen M. Roche
- Nutrigenomics Research GroupSchool of Public Health Physiotherapy and Sports ScienceUniversity College DublinDublin 4Ireland
- UCD Institute of Food and HealthUniversity College DublinDublin 4Ireland
| | - Fiona C. McGillicuddy
- UCD Institute of Food and HealthUniversity College DublinDublin 4Ireland
- Diabetes Complications Research CentreUCD Conway Institute and School of MedicineUniversity College DublinDublin 4Ireland
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Tall AR. Plasma high density lipoproteins: Therapeutic targeting and links to atherogenic inflammation. Atherosclerosis 2018; 276:39-43. [DOI: 10.1016/j.atherosclerosis.2018.07.004] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Revised: 06/19/2018] [Accepted: 07/03/2018] [Indexed: 11/16/2022]
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Abstract
PURPOSE OF REVIEW Leukocytosis, elevated blood leukocyte levels, is associated with enhanced cardiovascular risk in humans. Hematopoietic stem and progenitor cells (HSPCs) drive leukocyte production in a process called hematopoiesis, which mainly occurs in the bone marrow, and under certain conditions also in other organs such as the spleen. Cholesterol accumulation in HSPCs enhances hematopoiesis, increasing levels of blood monocytes that infiltrate into atherosclerotic plaques. Although HSPC proliferation and monocytosis enhance atherogenesis in several studies, concomitant decreases in LDL-cholesterol levels have also been reported, associated with anti-atherogenic effects. This review focuses on the link between HSPC proliferation, leukocytosis, plasma LDL-cholesterol levels, and atherogenesis. RECENT FINDINGS Recent studies have shown that an acute infection enhances cholesterol accumulation in HSPCs, driving HSPC proliferation, and leading to the expansion of myeloid cells (monocytes, neutrophils, and macrophages). Enhanced hematopoiesis is associated with low plasma LDL-cholesterol levels in animal models and humans, probably because of the increased number of myeloid cells that take up LDL-cholesterol. Despite low-plasma LDL-cholesterol levels, specific patient populations with enhanced hematopoiesis show increased cardiovascular risk. SUMMARY Enhanced hematopoiesis and monocytosis may accelerate atherogenesis. Studies on these processes may lead to the identification of new therapeutic targets for cardiovascular diseases.
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Affiliation(s)
- Venetia Bazioti
- Section of Molecular Genetics, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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Generoso G, Bensenor IM, Santos RD, Santos IS, Goulart AC, Jones SR, Kulkarni KR, Blaha MJ, Toth PP, Lotufo PA, Bittencourt MS. Association between high-density lipoprotein subfractions and low-grade inflammation, insulin resistance, and metabolic syndrome components: The ELSA-Brasil study. J Clin Lipidol 2018; 12:1290-1297.e1. [PMID: 29941395 DOI: 10.1016/j.jacl.2018.05.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Revised: 04/23/2018] [Accepted: 05/04/2018] [Indexed: 01/24/2023]
Abstract
BACKGROUND High-density lipoprotein cholesterol (HDL-C) can be divided into subfractions, which may have variable effects in atherogenesis. The results about the association between HDL-C subfractions and risk factors for cardiovascular disease are mixed. OBJECTIVE The objective of this study was to analyze the association between HDL-C subfractions and each metabolic syndrome component, homeostasis model assessment-estimated insulin resistance (HOMA-IR) and C-reactive protein (CRP). METHODS Four thousand five hundred thirty-two individuals between 35 and 74 years old without previous manifest cardiovascular disease not using fibrates were enrolled. HDL-C subfractions were separated by vertical ultracentrifugation (vertical auto profile-in mg/dL) into HDL2-C and HDL3-C. HDL2-C/HDL3-C ratio, HOMA-IR, and high-sensitivity CRP were also included in the analysis. RESULTS Mean age of participants was 51 ± 9 years, and 54.8% were women. In univariate analysis, HDL-C, HDL2-C, and HDL3-C were all inversely associated with each of the metabolic syndrome defining factors, HOMA-IR values, and serum CRP. We also observed a negative association between HDL2-C/HDL3-C ratio with the variables aforementioned even after adjusting for smoking, alcohol use, physical activity, and HDL-C levels (P < .01). CONCLUSION HDL-C and its subfractions (HDL2-C and HDL3-C) are inversely associated with the defining features of metabolic syndrome, insulin resistance, and systemic inflammation. In addition, the HDL2-C/HDL3-C ratio measured by vertical auto profile is significantly associated with the former factors even after comprehensive adjustment for HDL-C and other confounding variables.
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Affiliation(s)
- Giuliano Generoso
- Instituto do Coracao (InCor), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, Brazil; Center for Clinical and Epidemiological Research, University Hospital, University of São Paulo, São Paulo, Brazil
| | - Isabela M Bensenor
- Center for Clinical and Epidemiological Research, University Hospital, University of São Paulo, São Paulo, Brazil; Department of Internal Medicine, University of São Paulo Medical School, São Paulo, Brazil
| | - Raul D Santos
- Instituto do Coracao (InCor), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, Brazil
| | - Itamar S Santos
- Center for Clinical and Epidemiological Research, University Hospital, University of São Paulo, São Paulo, Brazil; Department of Internal Medicine, University of São Paulo Medical School, São Paulo, Brazil
| | - Alessandra C Goulart
- Center for Clinical and Epidemiological Research, University Hospital, University of São Paulo, São Paulo, Brazil
| | - Steven R Jones
- The Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Baltimore, MD, USA
| | | | - Michael J Blaha
- The Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Baltimore, MD, USA
| | - Peter P Toth
- The Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Baltimore, MD, USA; Preventive Cardiology, CGH Medical Center, Sterling, IL, USA
| | - Paulo A Lotufo
- Center for Clinical and Epidemiological Research, University Hospital, University of São Paulo, São Paulo, Brazil
| | - Marcio Sommer Bittencourt
- Center for Clinical and Epidemiological Research, University Hospital, University of São Paulo, São Paulo, Brazil.
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Su H, Wan C, Lei CT, Zhang CY, Ye C, Tang H, Qiu Y, Zhang C. Lipid Deposition in Kidney Diseases: Interplay Among Redox, Lipid Mediators, and Renal Impairment. Antioxid Redox Signal 2018; 28:1027-1043. [PMID: 28325081 DOI: 10.1089/ars.2017.7066] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Significance: The relationship between lipid disturbances and renal diseases has been studied for several decades, and it is well recognized that when the balance of renal lipid uptake, synthesis, oxidation, and outflow is disrupted, lipids will undergo oxidation, be sequestrated as lipid droplets, generate toxic metabolites, and cause nephrotoxicity in diverse renal diseases. Recent Advances: During renal disorders, redox signaling is a pivotal event promoting or resulting from lipid disorders. Accordingly, a vicious cycle of lipid redox dysregulation could be developed, accelerating the renal damage. Critical Issues: The aim of this concise review is to introduce the connection among redox, lipid abnormalities and kidney damage in various conditions. And we summarized current understanding of the lipid redox loop implicated in acute kidney injury, chronic kidney disease, metabolic abnormalities, aging, and genetic pitfalls. Future Directions: Despite recent advances, further investigations are required to clarify the complicated molecular and regulatory mechanisms among redox, lipid mediators and renal disorders. Moreover, exploring an ideal target for potential therapies should be discussed and studied in future. Antioxid. Redox Signal. 28, 1027-1043.
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Affiliation(s)
- Hua Su
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Cheng Wan
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chun-Tao Lei
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chun-Yun Zhang
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chen Ye
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hui Tang
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yue Qiu
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chun Zhang
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Yang Y, Yang Q, Yang J, Ma Y, Ding G. Angiotensin II induces cholesterol accumulation and injury in podocytes. Sci Rep 2017; 7:10672. [PMID: 28878222 PMCID: PMC5587570 DOI: 10.1038/s41598-017-09733-w] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Accepted: 07/28/2017] [Indexed: 12/14/2022] Open
Abstract
Angiotensin II (Ang II) is a risk factor for the initiation and progression of chronic kidney disease (CKD), as elevated Ang II levels can lead to podocyte injury. However, there have been no studies on the role of Ang II in lipid metabolism or on podocyte injury caused by lipid dysfunction. Our study showed that Ang II induced lipid droplet (LD) accumulation and expression of the LD marker adipose differentiation-related protein (ADRP) in podocytes, and the extent of lipid deposition could be alleviated by losartan. Our study also demonstrated that Ang II increased the content of cholesterol in podocytes, which is an LD component, and this change was accompanied by decreased expression of the cholesterol efflux-related molecule ATP-binding cassette transporter-1 (ABCA1) and increased expression of the cholesterol uptake-related molecule LDL receptor (LDLR) and the cholesterol synthesis-related molecules sterol regulatory element-binding protein (SREBP1 and SREBP2) and 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR). Pretreating podocytes with methyl-β-cyclodextrin (CD), which induces cholesterol efflux, decreased Ang II-mediated cholesterol accumulation and Ang II-induced podocyte apoptosis and maintained the podocyte cytoskeleton and spreading. These results suggested that Ang II induced podocyte cholesterol accumulation by regulating the expression of cholesterol metabolism-related molecules and that the subsequent cholesterol metabolism dysfunction resulted in podocyte injury.
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Affiliation(s)
- Yingjie Yang
- Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China
| | - Qian Yang
- Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China
| | - Jian Yang
- Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China
| | - Yiqiong Ma
- Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China
| | - Guohua Ding
- Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China.
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Barrett TJ, Murphy AJ, Goldberg IJ, Fisher EA. Diabetes-mediated myelopoiesis and the relationship to cardiovascular risk. Ann N Y Acad Sci 2017; 1402:31-42. [PMID: 28926114 PMCID: PMC5659728 DOI: 10.1111/nyas.13462] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Revised: 08/03/2017] [Accepted: 08/07/2017] [Indexed: 12/20/2022]
Abstract
Diabetes is the greatest risk factor for the development of cardiovascular disease, which, in turn, is the most prevalent cause of mortality and morbidity in diabetics. These patients have elevations in inflammatory monocytes, a factor consistently reported to drive the development of atherosclerosis. In preclinical models of both type 1 and type 2 diabetes, studies have demonstrated that the increased production and activation of monocytes is driven by enhanced myelopoiesis, promoted by factors, including hyperglycemia, impaired cholesterol efflux, and inflammasome activation, that affect the proliferation of bone marrow precursor cells. This suggests that continued mechanistic investigations of the enhanced myelopoiesis and the generation of inflammatory monocytes are timely, from the dual perspectives of understanding more deeply the underlying bases of diabetes pathophysiology and identifying therapeutic targets to reduce cardiovascular risk in these patients.
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Affiliation(s)
- Tessa J. Barrett
- Department of Medicine, Division of Cardiology, New York University
School of Medicine, New York, New York
| | - Andrew J. Murphy
- Haematopoiesis and Leukocyte Biology, Baker Heart and Diabetes
Institute, Melbourne, Australia
- Department of Immunology, Monash University, Melbourne,
Australia
| | - Ira J. Goldberg
- Department of Medicine, Division of Endocrinology, Diabetes and
Metabolism, New York University School of Medicine, New York, New York
| | - Edward A. Fisher
- Department of Medicine, Division of Cardiology, New York University
School of Medicine, New York, New York
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40
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Kain V, Halade GV. Metabolic and Biochemical Stressors in Diabetic Cardiomyopathy. Front Cardiovasc Med 2017; 4:31. [PMID: 28620607 PMCID: PMC5449449 DOI: 10.3389/fcvm.2017.00031] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Accepted: 04/28/2017] [Indexed: 12/18/2022] Open
Abstract
Diabetic cardiomyopathy (DCM) or diabetes-induced cardiac dysfunction is a direct consequence of uncontrolled metabolic syndrome and is widespread in US population and worldwide. Despite of the heterogeneous and distinct features of DCM, the clinical relevance of DCM is now becoming established. DCM progresses to pathological cardiac remodeling with the higher risk of heart attack and subsequent heart failure in diabetic patients. In this review, we emphasize lipid substrate quality and the phenotypic, metabolic, and biochemical stressors of DCM in the rodent and human pathophysiology. We discuss lipoxygenase signaling in the inflammatory pathway with multiple contributing and confounding factors leading to DCM. Additionally, emerging biochemical pathways are emphasized to make progress toward therapeutic advancement to treat DCM.
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Affiliation(s)
- Vasundhara Kain
- Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Ganesh V Halade
- Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
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41
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Yin QH, Zhang R, Li L, Wang YT, Liu JP, Zhang J, Bai L, Cheng JQ, Fu P, Liu F. Exendin-4 Ameliorates Lipotoxicity-induced Glomerular Endothelial Cell Injury by Improving ABC Transporter A1-mediated Cholesterol Efflux in Diabetic apoE Knockout Mice. J Biol Chem 2016; 291:26487-26501. [PMID: 27784780 DOI: 10.1074/jbc.m116.730564] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Revised: 10/22/2016] [Indexed: 02/05/2023] Open
Abstract
ATP-binding cassette transporter A1 (ABCA1), which promotes cholesterol efflux from cells and inhibits inflammatory responses, is highly expressed in the kidney. Research has shown that exendin-4, a glucagon-like peptide-1 receptor (GLP-1R) agonist, promotes ABCA1 expression in multiple tissues and organs; however, the mechanisms underlying exendin-4 induction of ABCA1 expression in glomerular endothelial cells are not fully understood. In this study we investigated the effect of exendin-4 on ABCA1 in glomerular endothelial cells of diabetic kidney disease (DKD) and the possible mechanism. We observed a marked increase in glomerular lipid deposits in tissues of patients with DKD and diabetic apolipoprotein E knock-out (apoE-/-) mice by Oil Red O staining and biochemical analysis of cholesterol. We found significantly decreased ABCA1 expression in glomerular endothelial cells of diabetic apoE-/- mice and increased renal lipid, cholesterol, and inflammatory cytokine levels. Exendin-4 decreased renal cholesterol accumulation and inflammation and increased cholesterol efflux by up-regulating ABCA1. In human glomerular endothelial cells, GLP-1R-mediated signaling pathways (e.g. Ca2+/calmodulin-dependent protein kinase, cAMP/PKA, PI3K/AKT, and ERK1/2) were involved in cholesterol efflux and inflammatory responses by regulating ABCA1 expression. We propose that exendin-4 increases ABCA1 expression in glomerular endothelial cells, which plays an important role in alleviating renal lipid accumulation, inflammation, and proteinuria in mice with type 2 diabetes.
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Affiliation(s)
- Qing-Hua Yin
- From the Division of Nephrology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China and
| | - Rui Zhang
- From the Division of Nephrology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China and
| | - Li Li
- From the Division of Nephrology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China and
| | - Yi-Ting Wang
- From the Division of Nephrology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China and
| | - Jing-Ping Liu
- the Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, Regenerative Medicine Research Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China
| | - Jie Zhang
- the Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, Regenerative Medicine Research Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China
| | - Lin Bai
- the Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, Regenerative Medicine Research Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China
| | - Jing-Qiu Cheng
- the Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, Regenerative Medicine Research Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China
| | - Ping Fu
- From the Division of Nephrology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China and
| | - Fang Liu
- From the Division of Nephrology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China and
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42
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Obesity-related glomerulopathy: clinical and pathologic characteristics and pathogenesis. Nat Rev Nephrol 2016; 12:453-71. [PMID: 27263398 DOI: 10.1038/nrneph.2016.75] [Citation(s) in RCA: 470] [Impact Index Per Article: 52.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The prevalence of obesity-related glomerulopathy is increasing in parallel with the worldwide obesity epidemic. Glomerular hypertrophy and adaptive focal segmental glomerulosclerosis define the condition pathologically. The glomerulus enlarges in response to obesity-induced increases in glomerular filtration rate, renal plasma flow, filtration fraction and tubular sodium reabsorption. Normal insulin/phosphatidylinositol 3-kinase/Akt and mTOR signalling are critical for podocyte hypertrophy and adaptation. Adipokines and ectopic lipid accumulation in the kidney promote insulin resistance of podocytes and maladaptive responses to cope with the mechanical forces of renal hyperfiltration. Although most patients have stable or slowly progressive proteinuria, up to one-third develop progressive renal failure and end-stage renal disease. Renin-angiotensin-aldosterone blockade is effective in the short-term but weight loss by hypocaloric diet or bariatric surgery has induced more consistent and dramatic antiproteinuric effects and reversal of hyperfiltration. Altered fatty acid and cholesterol metabolism are increasingly recognized as key mediators of renal lipid accumulation, inflammation, oxidative stress and fibrosis. Newer therapies directed to lipid metabolism, including SREBP antagonists, PPARα agonists, FXR and TGR5 agonists, and LXR agonists, hold therapeutic promise.
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43
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Murphy AJ, Tall AR. Disordered haematopoiesis and athero-thrombosis. Eur Heart J 2016; 37:1113-21. [PMID: 26869607 PMCID: PMC4823636 DOI: 10.1093/eurheartj/ehv718] [Citation(s) in RCA: 78] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Revised: 11/22/2015] [Accepted: 12/07/2015] [Indexed: 12/25/2022] Open
Abstract
Atherosclerosis, the major underlying cause of cardiovascular disease, is characterized by a lipid-driven infiltration of inflammatory cells in large and medium arteries. Increased production and activation of monocytes, neutrophils, and platelets, driven by hypercholesterolaemia and defective high-density lipoproteins-mediated cholesterol efflux, tissue necrosis and cytokine production after myocardial infarction, or metabolic abnormalities associated with diabetes, contribute to atherogenesis and athero-thrombosis. This suggests that in addition to traditional approaches of low-density lipoproteins lowering and anti-platelet drugs, therapies directed at abnormal haematopoiesis, including anti-inflammatory agents, drugs that suppress myelopoiesis, and excessive platelet production, rHDL infusions and anti-obesity and anti-diabetic agents, may help to prevent athero-thrombosis.
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Affiliation(s)
- Andrew J Murphy
- Haematopoiesis and Leukocyte Biology, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia Department of Immunology, Monash University, Melbourne, Victoria 3165, Australia
| | - Alan R Tall
- Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY 10032, USA
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44
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Wahl P, Ducasa GM, Fornoni A. Systemic and renal lipids in kidney disease development and progression. Am J Physiol Renal Physiol 2016; 310:F433-45. [PMID: 26697982 PMCID: PMC4971889 DOI: 10.1152/ajprenal.00375.2015] [Citation(s) in RCA: 92] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Accepted: 12/22/2015] [Indexed: 12/14/2022] Open
Abstract
Altered lipid metabolism characterizes proteinuria and chronic kidney diseases. While it is thought that dyslipidemia is a consequence of kidney disease, a large body of clinical and experimental studies support that altered lipid metabolism may contribute to the pathogenesis and progression of kidney disease. In fact, accumulation of renal lipids has been observed in several conditions of genetic and nongenetic origins, linking local fat to the pathogenesis of kidney disease. Statins, which target cholesterol synthesis, have not been proven beneficial to slow the progression of chronic kidney disease. Therefore, other therapeutic strategies to reduce cholesterol accumulation in peripheral organs, such as the kidney, warrant further investigation. Recent advances in the understanding of the biology of high-density lipoprotein (HDL) have revealed that functional HDL, rather than total HDL per se, may protect from both cardiovascular and kidney diseases, strongly supporting a role for altered cholesterol efflux in the pathogenesis of kidney disease. Although the underlying pathophysiological mechanisms responsible for lipid-induced renal damage have yet to be uncovered, several studies suggest novel mechanisms by which cholesterol, free fatty acids, and sphingolipids may affect glomerular and tubular cell function. This review will focus on the clinical and experimental evidence supporting a causative role of lipids in the pathogenesis of proteinuria and kidney disease, with a primary focus on podocytes.
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Affiliation(s)
- Patricia Wahl
- Peggy and Harold Katz Family Drug Discovery Center and Division of Nephrology and Hypertension, University of Miami Miller School of Medicine, Miami, Florida
| | - Gloria Michelle Ducasa
- Peggy and Harold Katz Family Drug Discovery Center and Division of Nephrology and Hypertension, University of Miami Miller School of Medicine, Miami, Florida
| | - Alessia Fornoni
- Peggy and Harold Katz Family Drug Discovery Center and Division of Nephrology and Hypertension, University of Miami Miller School of Medicine, Miami, Florida
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Cholesterol Transporters ABCA1 and ABCG1 Gene Expression in Peripheral Blood Mononuclear Cells in Patients with Metabolic Syndrome. CHOLESTEROL 2015; 2015:682904. [PMID: 26788366 PMCID: PMC4692991 DOI: 10.1155/2015/682904] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/16/2015] [Revised: 10/24/2015] [Accepted: 11/17/2015] [Indexed: 01/09/2023]
Abstract
ABCA1 and ABCG1 genes encode the cholesterol transporter proteins that play a key role in cholesterol and phospholipids homeostasis. This study was aimed at evaluating and comparing ABCA1 and ABCG1 genes expression in metabolic syndrome patients and healthy individuals. This case-control study was performed on 36 patients with metabolic syndrome and the same number of healthy individuals in Hamadan (west of Iran) during 2013-2014. Total RNA was extracted from mononuclear cells and purified using RNeasy Mini Kit column. The expression of ABCA1 and ABCG1 genes was performed by qRT-PCR. Lipid profile and fasting blood glucose were measured using colorimetric procedures. ABCG1 expression in metabolic syndrome patients was significantly lower (about 75%) compared to that of control group, while for ABCA1 expression, there was no significant difference between the two studied groups. Comparison of other parameters such as HDL-C, FBS, BMI, waist circumference, and systolic and diastolic blood pressure between metabolic syndrome patients and healthy individuals showed significant differences (P < 0.05). Decrease in ABCG1 expression in metabolic syndrome patients compared to healthy individuals suggests that hyperglycemia, related metabolites, and hyperlipidemia over the transporter capacity resulted in decreased expression of ABCG1. Absence of a significant change in ABCA1 gene expression between two groups can indicate a different regulation mechanism for ABCA1 expression.
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Daffu G, Shen X, Senatus L, Thiagarajan D, Abedini A, Hurtado Del Pozo C, Rosario R, Song F, Friedman RA, Ramasamy R, Schmidt AM. RAGE Suppresses ABCG1-Mediated Macrophage Cholesterol Efflux in Diabetes. Diabetes 2015; 64:4046-60. [PMID: 26253613 PMCID: PMC4657581 DOI: 10.2337/db15-0575] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Accepted: 07/23/2015] [Indexed: 01/13/2023]
Abstract
Diabetes exacerbates cardiovascular disease, at least in part through suppression of macrophage cholesterol efflux and levels of the cholesterol transporters ATP binding cassette transporter A1 (ABCA1) and ABCG1. The receptor for advanced glycation end products (RAGE) is highly expressed in human and murine diabetic atherosclerotic plaques, particularly in macrophages. We tested the hypothesis that RAGE suppresses macrophage cholesterol efflux and probed the mechanisms by which RAGE downregulates ABCA1 and ABCG1. Macrophage cholesterol efflux to apolipoprotein A1 and HDL and reverse cholesterol transport to plasma, liver, and feces were reduced in diabetic macrophages through RAGE. In vitro, RAGE ligands suppressed ABCG1 and ABCA1 promoter luciferase activity and transcription of ABCG1 and ABCA1 through peroxisome proliferator-activated receptor-γ (PPARG)-responsive promoter elements but not through liver X receptor elements. Plasma levels of HDL were reduced in diabetic mice in a RAGE-dependent manner. Laser capture microdissected CD68(+) macrophages from atherosclerotic plaques of Ldlr(-/-) mice devoid of Ager (RAGE) displayed higher levels of Abca1, Abcg1, and Pparg mRNA transcripts versus Ager-expressing Ldlr(-/-) mice independently of glycemia or plasma levels of total cholesterol and triglycerides. Antagonism of RAGE may fill an important therapeutic gap in the treatment of diabetic macrovascular complications.
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MESH Headings
- ATP Binding Cassette Transporter 1/genetics
- ATP Binding Cassette Transporter 1/metabolism
- ATP Binding Cassette Transporter, Subfamily G, Member 1
- ATP-Binding Cassette Transporters/antagonists & inhibitors
- ATP-Binding Cassette Transporters/genetics
- ATP-Binding Cassette Transporters/metabolism
- Animals
- Aorta/immunology
- Aorta/metabolism
- Aorta/pathology
- Biological Transport
- Cell Line
- Cells, Cultured
- Cholesterol/metabolism
- Diabetic Angiopathies/blood
- Diabetic Angiopathies/immunology
- Diabetic Angiopathies/metabolism
- Diabetic Angiopathies/pathology
- Glycation End Products, Advanced/blood
- Glycation End Products, Advanced/metabolism
- Humans
- Ligands
- Lipoproteins/antagonists & inhibitors
- Lipoproteins/genetics
- Lipoproteins/metabolism
- Macrophages/cytology
- Macrophages/immunology
- Macrophages/metabolism
- Macrophages/pathology
- Male
- Mice, Knockout
- PPAR gamma/genetics
- PPAR gamma/metabolism
- Plaque, Atherosclerotic/blood
- Plaque, Atherosclerotic/immunology
- Plaque, Atherosclerotic/metabolism
- Plaque, Atherosclerotic/pathology
- Promoter Regions, Genetic
- Receptor for Advanced Glycation End Products/agonists
- Receptor for Advanced Glycation End Products/blood
- Receptor for Advanced Glycation End Products/genetics
- Receptor for Advanced Glycation End Products/metabolism
- Recombinant Proteins/chemistry
- Recombinant Proteins/metabolism
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Affiliation(s)
- Gurdip Daffu
- Diabetes Research Program, Division of Endocrinology, Department of Medicine, New York University School of Medicine, New York, NY
| | - Xiaoping Shen
- Diabetes Research Program, Division of Endocrinology, Department of Medicine, New York University School of Medicine, New York, NY
| | - Laura Senatus
- Diabetes Research Program, Division of Endocrinology, Department of Medicine, New York University School of Medicine, New York, NY
| | - Devi Thiagarajan
- Diabetes Research Program, Division of Endocrinology, Department of Medicine, New York University School of Medicine, New York, NY
| | - Andisheh Abedini
- Diabetes Research Program, Division of Endocrinology, Department of Medicine, New York University School of Medicine, New York, NY
| | - Carmen Hurtado Del Pozo
- Diabetes Research Program, Division of Endocrinology, Department of Medicine, New York University School of Medicine, New York, NY
| | - Rosa Rosario
- Diabetes Research Program, Division of Endocrinology, Department of Medicine, New York University School of Medicine, New York, NY
| | - Fei Song
- Diabetes Research Program, Division of Endocrinology, Department of Medicine, New York University School of Medicine, New York, NY
| | - Richard A Friedman
- Biomedical Informatics Shared Resource, Herbert Irving Comprehensive Cancer Center, and Department of Biomedical Informatics, College of Physicians and Surgeons, Columbia University, New York, NY
| | - Ravichandran Ramasamy
- Diabetes Research Program, Division of Endocrinology, Department of Medicine, New York University School of Medicine, New York, NY
| | - Ann Marie Schmidt
- Diabetes Research Program, Division of Endocrinology, Department of Medicine, New York University School of Medicine, New York, NY
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Allen TJ, Murphy AJ, Jandeleit-Dahm KA. RAGE Against the ABCs. Diabetes 2015; 64:3981-3. [PMID: 26604171 DOI: 10.2337/dbi15-0015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Affiliation(s)
- Terri J Allen
- Biochemistry of Diabetic Complications Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Australia Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia
| | - Andrew J Murphy
- Hematopoiesis and Leukocyte Biology Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Australia Department of Immunology, Monash University, Melbourne, Australia
| | - Karin A Jandeleit-Dahm
- Biochemistry of Diabetic Complications Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Australia Department of Medicine, Monash University, Melbourne, Australia
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Du C, Shi Y, Ren Y, Wu H, Yao F, Wei J, Wu M, Hou Y, Duan H. Anthocyanins inhibit high-glucose-induced cholesterol accumulation and inflammation by activating LXRα pathway in HK-2 cells. DRUG DESIGN DEVELOPMENT AND THERAPY 2015; 9:5099-113. [PMID: 26379423 PMCID: PMC4567235 DOI: 10.2147/dddt.s90201] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The dysregulation of cholesterol metabolism and inflammation plays a significant role in the progression of diabetic nephropathy (DN). Anthocyanins are polyphenols widely distributed in food and exert various biological effects including antioxidative, anti-inflammatory, and antihyperlipidemic effects. However, it remains unclear whether anthocyanins are associated with DN, and the mechanisms involved in the reciprocal regulation of inflammation and cholesterol efflux are yet to be elucidated. In this study, we evaluated the regulation of cholesterol metabolism and the anti-inflammatory effects exerted by anthocyanins (cyanidin-3-O-β-glucoside chloride [C3G] or cyanidin chloride [Cy]) and investigated the underlying molecular mechanism of action using high-glucose (HG)-stimulated HK-2 cells. We found that anthocyanins enhanced cholesterol efflux and ABCA1 expression markedly in HK-2 cells. In addition, they increased peroxisome proliferator-activated receptor alpha (PPARα) and liver X receptor alpha (LXRα) expression and decreased the HG-induced expression of the proinflammatory cytokines intercellular adhesion molecule-1 (ICAM1), monocyte chemoattractant protein-1 (MCP1), and transforming growth factor-β1 (TGFβ1), as well as NFκB activation. Incubation with the PPARα-specific inhibitor GW6471 and LXRα shRNA attenuated the anthocyanin-mediated promotion of ABCA1 expression and cholesterol efflux, suggesting that anthocyanins activated PPARα-LXRα-ABCA1-dependent cholesterol efflux in HK-2 cells. Moreover, the knockout of LXRα abrogated the anti-inflammatory effect of anthocyanins, whereas the PPARα antagonist GW6471 does not have this effect. Further investigations revealed that LXRα might interfere with anthocyanin-induced decreased ICAM1, MCP1, and TGFβ1 expression by reducing the nuclear translocation of NFκB. Collectively, these findings suggest that blocking cholesterol deposition and inhibiting the LXRα pathway-induced inflammatory response might be one of the main mechanisms by which anthocyanins exert their protective effects in DN.
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Affiliation(s)
- Chunyang Du
- Department of Pathology, Hebei Medical University, Shijiazhuang, People's Republic of China ; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, People's Republic of China
| | - Yonghong Shi
- Department of Pathology, Hebei Medical University, Shijiazhuang, People's Republic of China ; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, People's Republic of China
| | - Yunzhuo Ren
- Department of Pathology, Hebei Medical University, Shijiazhuang, People's Republic of China ; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, People's Republic of China
| | - Haijiang Wu
- Department of Pathology, Hebei Medical University, Shijiazhuang, People's Republic of China ; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, People's Republic of China
| | - Fang Yao
- Department of Pathology, Hebei Medical University, Shijiazhuang, People's Republic of China ; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, People's Republic of China
| | - Jinying Wei
- Department of Pathology, Hebei Medical University, Shijiazhuang, People's Republic of China ; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, People's Republic of China
| | - Ming Wu
- Department of Pathology, Hebei Medical University, Shijiazhuang, People's Republic of China ; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, People's Republic of China
| | - Yanjuan Hou
- Department of Pathology, Hebei Medical University, Shijiazhuang, People's Republic of China ; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, People's Republic of China
| | - Huijun Duan
- Department of Pathology, Hebei Medical University, Shijiazhuang, People's Republic of China ; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, People's Republic of China
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50
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Fuentes-Antrás J, Picatoste B, Gómez-Hernández A, Egido J, Tuñón J, Lorenzo Ó. Updating experimental models of diabetic cardiomyopathy. J Diabetes Res 2015; 2015:656795. [PMID: 25973429 PMCID: PMC4417999 DOI: 10.1155/2015/656795] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2015] [Revised: 03/26/2015] [Accepted: 03/29/2015] [Indexed: 11/17/2022] Open
Abstract
Diabetic cardiomyopathy entails a serious cardiac dysfunction induced by alterations in structure and contractility of the myocardium. This pathology is initiated by changes in energy substrates and occurs in the absence of atherothrombosis, hypertension, or other cardiomyopathies. Inflammation, hypertrophy, fibrosis, steatosis, and apoptosis in the myocardium have been studied in numerous diabetic experimental models in animals, mostly rodents. Type I and type II diabetes were induced by genetic manipulation, pancreatic toxins, and fat and sweet diets, and animals recapitulate the main features of human diabetes and related cardiomyopathy. In this review we update and discuss the main experimental models of diabetic cardiomyopathy, analysing the associated metabolic, structural, and functional abnormalities, and including current tools for detection of these responses. Also, novel experimental models based on genetic modifications of specific related genes have been discussed. The study of specific pathways or factors responsible for cardiac failures may be useful to design new pharmacological strategies for diabetic patients.
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Affiliation(s)
- J. Fuentes-Antrás
- IIS-Fundación Jiménez Díaz, Autónoma University, 28040 Madrid, Spain
| | - B. Picatoste
- IIS-Fundación Jiménez Díaz, Autónoma University, 28040 Madrid, Spain
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM) Network, 28040 Madrid, Spain
| | - A. Gómez-Hernández
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM) Network, 28040 Madrid, Spain
- Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid, 28040 Madrid, Spain
| | - J. Egido
- IIS-Fundación Jiménez Díaz, Autónoma University, 28040 Madrid, Spain
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM) Network, 28040 Madrid, Spain
| | - J. Tuñón
- IIS-Fundación Jiménez Díaz, Autónoma University, 28040 Madrid, Spain
| | - Ó. Lorenzo
- IIS-Fundación Jiménez Díaz, Autónoma University, 28040 Madrid, Spain
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM) Network, 28040 Madrid, Spain
- *Ó. Lorenzo:
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