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Li X, Li L, Tian J, Su R, Sun J, Li Y, Wang L, Zhou H, Sha S, Xiao J, Dong H, Huo C, Hu Y, Yang H. SREBP2-dependent lipid droplet formation enhances viral replication and deteriorates lung injury in mice following IAV infection. Emerg Microbes Infect 2025; 14:2470371. [PMID: 39968754 PMCID: PMC11873989 DOI: 10.1080/22221751.2025.2470371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 01/27/2025] [Accepted: 02/16/2025] [Indexed: 02/20/2025]
Abstract
Influenza A virus (IAV) is a significant zoonotic pathogen that poses a considerable challenge to public health due to its continuous mutations. Lipid droplets (LDs) have been shown to play an important role in the process of several viral infections. However, their role in IAV infection remains unclear. Here, we found that IAV infection altered the lipid metabolism and increased the content of LDs in the lungs of mice. In vitro, IAV infection also mediated the formation of LDs in A549 cells. Besides, inhibition of the formation of lipid droplets can significantly suppress IAV replication and the release of inflammatory factors, indicating that LDs could facilitate the virus replication and inflammatory response. Furthermore, we discovered that IAV infection could activate the SREBP2, a crucial lipid-regulating transcription factor that regulates the expressions of downstream proteins named HMGCR and HMGCS. HMGCR and HMGCS involved in the process of cholesterol synthesis, which further promoted the formation of LDs. Additionally, the use of fatostatin that specifically inhibits the maturation of SREBP2 was able to significantly suppress the viral replication of H5N1 in cells and effectively ameliorated IAV-induced lung injury in mice, which eventually promoted the survival rate of infected mice. Taken together, we demonstrate the essential roles of lipid metabolism and LD formation in IAV replication and pathogenesis, which may better facilitate the advancement of new strategies against IAV infection, especially the highly pathogenic H5N1 virus.
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Affiliation(s)
- Xinsen Li
- National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory of Animal Epidemiology of Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, People’s Republic of China
| | - Lu Li
- Infectious Disease Department, Peking University Third Hospital, Beijing, People’s Republic of China
| | - Jijing Tian
- National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory of Animal Epidemiology of Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, People’s Republic of China
| | - Ruijing Su
- National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory of Animal Epidemiology of Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, People’s Republic of China
| | - Jiali Sun
- National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory of Animal Epidemiology of Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, People’s Republic of China
| | - Yuli Li
- National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory of Animal Epidemiology of Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, People’s Republic of China
| | - Lige Wang
- National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory of Animal Epidemiology of Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, People’s Republic of China
| | - Hongye Zhou
- National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory of Animal Epidemiology of Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, People’s Republic of China
| | - Shuhan Sha
- National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory of Animal Epidemiology of Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, People’s Republic of China
| | - Jin Xiao
- Key Laboratory of Veterinary Bioproduction and Chemical Medicine of the Ministry of Agriculture, Zhongmu Institutes of China Animal Husbandry Industry Co., Ltd, Beijing, People’s Republic of China
| | - Hong Dong
- Beijing Key Laboratory of Traditional Chinese Veterinary Medicine, Beijing University of Agriculture, Beijing, People’s Republic of China
| | - Caiyun Huo
- National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory of Animal Epidemiology of Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, People’s Republic of China
| | - Yanxin Hu
- National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory of Animal Epidemiology of Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, People’s Republic of China
| | - Hanchun Yang
- National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory of Animal Epidemiology of Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, People’s Republic of China
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2
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He Y, Jiang J, Ou L, Chen Y, Abudukeremu A, Chen G, Zhong W, Jiang Z, Nuermaimaiti N, Guan Y. Impaired RelA signaling and lipid metabolism dysregulation in hepatocytes: driving forces in the progression of metabolic dysfunction-associated steatotic liver disease. Cell Death Discov 2025; 11:49. [PMID: 39910053 PMCID: PMC11799324 DOI: 10.1038/s41420-025-02312-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 12/25/2024] [Accepted: 01/21/2025] [Indexed: 02/07/2025] Open
Abstract
RelA, also known as nuclear factor kappa B p65, plays a crucial role in the pathogenesis of various liver diseases. However, the specific role of RelA in hepatocytes during the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) is not well understood. This study explored the relationship between impaired RelA signaling and lipid metabolism disorders in hepatocytes, and how they synergistically contribute to the advancement of MASLD. We assessed the changes, regulatory relationships, and impacts of RelA signaling and lipid metabolism remodeling on disease progression both in vitro and in vivo. During MASLD, there was a decrease in the expression of RelA and hepatocyte nuclear factor 1 alpha (HNF1α), with both factors showing mutual enhancement of each other's expression under normal conditions. This synergistic effect was absent during hepatocyte steatosis. RelA or HNF1α depletion in hepatocytes intensified MASLD symptoms, whereas overexpression of RELA or treatment with necrostatin-1 (a necroptosis inhibitor) or Z-VAD (a caspase inhibitor) significantly mitigated these effects. Mechanistically, during hepatic steatosis, altered lipid profiles exhibited lipotoxicity, inducing hepatocyte apoptosis and necroptosis, whereas endoplasmic reticulum (ER) stress triggered lipid remodeling processes similar to those observed in MASLD. RelA signaling upregulated the expression of activating transcription factor 4 and glucose-regulated protein 78, thereby alleviating ER stress. Impaired RelA signaling remodeled the ER stress response and lipid metabolism, and enhanced lipid accumulation and lipid toxicity. In conclusion, impaired RelA signaling and disrupted lipid metabolism form a detrimental feedback loop in hepatocytes that promotes MASLD progression. Lipid accumulation suppresses RelA signaling, remodeling the ER stress response and exacerbating lipid metabolism disorder, ultimately leading to hepatocyte apoptosis and necroptosis.
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Affiliation(s)
- Yihuai He
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Key Laboratory of Molecular Biology for Endemic Diseases, Department of Pathology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, Xinjiang, China
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Jinlian Jiang
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Lili Ou
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Yunfen Chen
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Aikedaimu Abudukeremu
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Key Laboratory of Molecular Biology for Endemic Diseases, Department of Pathology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Guimei Chen
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Weiwei Zhong
- Department of Infectious Diseases, Jingmen Central Hospital, Jingmen, Hubei, China
| | - Zhigang Jiang
- School of Public Health, Zunyi Medical University, Zunyi, Guizhou, China
| | - Nuerbiye Nuermaimaiti
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Key Laboratory of Molecular Biology for Endemic Diseases, Department of Pathology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Yaqun Guan
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Key Laboratory of Molecular Biology for Endemic Diseases, Department of Pathology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, Xinjiang, China.
- Xinjiang Second Medical College, Karamay, Xinjiang, China.
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3
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Zhang L, Fang Z, Zhu Q, Yang S, Fu J, Sun Z, Lu G, Wei C, Zhang Z, Lee K, Zhong Y, Liu R, He JC. Cholesterol 25-Hydroxylase Protects Against Diabetic Kidney Disease by Regulating ADP Ribosylation Factor 4. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2309642. [PMID: 38816950 PMCID: PMC11304234 DOI: 10.1002/advs.202309642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Revised: 03/30/2024] [Indexed: 06/01/2024]
Abstract
Cholesterol 25-hydroxylase (CH25H), an enzyme involved in cholesterol metabolism, regulates inflammatory responses and lipid metabolism. However, its role in kidney disease is not known. The author found that CH25H transcript is expressed mostly in glomerular and peritubular endothelial cells and that its expression increased in human and mouse diabetic kidneys. Global deletion of Ch25h in Leprdb/db mice aggravated diabetic kidney disease (DKD), which is associated with increased endothelial cell apoptosis. Treatment of 25-hydroxycholesterol (25-HC), the product of CH25H, alleviated kidney injury in Leprdb/db mice. Mechanistically, 25-HC binds to GTP-binding protein ADP-ribosylation factor 4 (ARF4), an essential protein required for maintaining protein transport in the Golgi apparatus. Interestingly, ARF4's GTPase-activating protein ASAP1 is also predominantly expressed in endothelial cells and its expression increased in DKD. Suppression of ARF4 activity by deleting ARF4 or overexpressing ASAP1 results in endothelial cell death. These results indicate that 25-HC binds ARF4 to inhibit its interaction with ASAP1, and thereby resulting in enhanced ARF4 activity to confer renoprotection. Therefore, treatment of 25-HC improves kidney injury in DKD in part by restoring ARF4 activity to maintain endothelial cell survival. This study provides a novel mechanism and a potential new therapy for DKD.
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Affiliation(s)
- Lu Zhang
- Department of MedicineDivision of NephrologyIcahn School of Medicine at Mount SinaiNew YorkNYBox 1243USA
| | - Zhengying Fang
- Department of MedicineDivision of NephrologyIcahn School of Medicine at Mount SinaiNew YorkNYBox 1243USA
| | - Qingqing Zhu
- Department of MedicineDivision of NephrologyIcahn School of Medicine at Mount SinaiNew YorkNYBox 1243USA
| | - Shumin Yang
- Department of MedicineDivision of NephrologyIcahn School of Medicine at Mount SinaiNew YorkNYBox 1243USA
| | - Jia Fu
- Department of MedicineDivision of NephrologyIcahn School of Medicine at Mount SinaiNew YorkNYBox 1243USA
| | - Zeguo Sun
- Department of MedicineDivision of NephrologyIcahn School of Medicine at Mount SinaiNew YorkNYBox 1243USA
| | - Geming Lu
- Division of EndocrinologyDiabetes and Bone DiseasesIcahn School of Medicine at Mount SinaiDiabetesObesity and Metabolism InstituteOne Gustave L. Levy PlaceNew YorkNY10029USA
| | - Chengguo Wei
- Department of MedicineDivision of NephrologyIcahn School of Medicine at Mount SinaiNew YorkNYBox 1243USA
| | - Zhi Zhang
- Département de Génétique Laboratoire national de santé DudelangeDudelangeL‐3555Luxembourg
| | - Kyung Lee
- Department of MedicineDivision of NephrologyIcahn School of Medicine at Mount SinaiNew YorkNYBox 1243USA
| | - Yifei Zhong
- Division of NephrologyLonghua HospitalShanghai University of Traditional Chinese Medicine725 South Wanping RoadShanghai200032China
| | - Ruijie Liu
- Department of MedicineDivision of NephrologyIcahn School of Medicine at Mount SinaiNew YorkNYBox 1243USA
| | - John Cijiang He
- Department of MedicineDivision of NephrologyIcahn School of Medicine at Mount SinaiNew YorkNYBox 1243USA
- Renal SectionJames J Peter Veterans Administration Medical CenterBronxNY10468USA
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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: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [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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Trink J, Nmecha IK, Zhang D, MacDonald M, Gao B, Krepinsky JC. Both sexes develop DKD in the CD1 uninephrectomized streptozotocin mouse model. Sci Rep 2023; 13:16635. [PMID: 37789041 PMCID: PMC10547794 DOI: 10.1038/s41598-023-42670-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 09/12/2023] [Indexed: 10/05/2023] Open
Abstract
Diabetic kidney disease (DKD) is characterized by a progressive increase in albuminuria and typical pathologic features. Recent studies have shown that sex is an important factor to consider in the pathogenesis of DKD. Presently, the hallmarks of this disease have primarily been studied in male rodent models. Here we explored the influence of sex in a murine model of DKD. CD1 mice underwent a right nephrectomy followed by intraperitoneal injection with 200 mg/kg streptozotocin to induce type 1 diabetes. Due to a high mortality rate, females required a reduction in streptozotocin to 150 mg/kg. Mice were followed for 12 weeks. Both sexes developed comparable hyperglycemia, while albuminuria and glomerular volume were increased to a greater degree in females and kidney hypertrophy was only seen in females. Males had a greater increase in blood pressure and glomerular basement membrane thickening, and a greater decrease in endpoint weight. Serum TGFβ1 levels were increased only in females. However, both sexes showed a similar increase in induction of kidney fibrosis. T cell and macrophage infiltration were also increased in both sexes. While some differences were observed, overall, both sexes developed clinical and pathologic characteristics of early DKD. Future studies evaluating therapeutic interventions can thus be assessed in both sexes of this DKD model.
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Affiliation(s)
- Jackie Trink
- Division of Nephrology, St. Joseph's Hospital, McMaster University, 50 Charlton Ave East, Rm T3311, Hamilton, ON, L8N 4A6, Canada
| | - Ifeanyi Kennedy Nmecha
- Division of Nephrology, St. Joseph's Hospital, McMaster University, 50 Charlton Ave East, Rm T3311, Hamilton, ON, L8N 4A6, Canada
| | - Dan Zhang
- Division of Nephrology, St. Joseph's Hospital, McMaster University, 50 Charlton Ave East, Rm T3311, Hamilton, ON, L8N 4A6, Canada
| | - Melissa MacDonald
- Division of Nephrology, St. Joseph's Hospital, McMaster University, 50 Charlton Ave East, Rm T3311, Hamilton, ON, L8N 4A6, Canada
| | - Bo Gao
- Division of Nephrology, St. Joseph's Hospital, McMaster University, 50 Charlton Ave East, Rm T3311, Hamilton, ON, L8N 4A6, Canada
| | - Joan C Krepinsky
- Division of Nephrology, St. Joseph's Hospital, McMaster University, 50 Charlton Ave East, Rm T3311, Hamilton, ON, L8N 4A6, Canada.
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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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Zuzda K, Grycuk W, Małyszko J, Małyszko J. Kidney and lipids: novel potential therapeutic targets for dyslipidemia in kidney disease? Expert Opin Ther Targets 2022; 26:995-1009. [PMID: 36548906 DOI: 10.1080/14728222.2022.2161887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Altered lipid distribution and metabolism may lead to the development and/or progression of chronic kidney disease (CKD). Dyslipidemia is a major risk factor for CKD and increases the risk of cardiovascular events and mortality. Therefore, lipid-lowering treatments may decrease cardiovascular risk and prevent death. AREAS COVERED Key players involved in regulating lipid accumulation in the kidney; contribution of lipids to CKD progression, lipotoxicity, and mitochondrial dysfunction in kidney disease; recent therapeutic approaches for dyslipidemia. EXPERT OPINION The precise mechanisms for regulating lipid metabolism, particularly in kidney disease, are poorly understood. Guidelines for lipid-lowering therapy for CKD are controversial. Several hypolipemic therapies are available, but compared to others, statin therapy is the most common. No clinical trial has evaluated the efficacy of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) in preventing cardiovascular events or improving kidney function among patients with CKD or kidney transplant recipients. Attractive alternatives, such as PCSK9-small interfering RNA (siRNA) molecules or evinacumab are available. Additionally, several promising agents, such as cyclodextrins and the FXR/TGR5 dual agonist, INT-767, can improve renal lipid metabolism disorders and delay CKD progression. Drugs targeting mitochondrial dysfunction could be an option for the treatment of dyslipidemia and lipotoxicity, particularly in renal diseases.
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Affiliation(s)
- Konrad Zuzda
- Department of Nephrology, Dialysis and Internal Medicine, Medical University of Warsaw, Bialystok, Poland
| | - Wiktoria Grycuk
- Department of Nephrology, Dialysis and Internal Medicine, Medical University of Warsaw, Bialystok, Poland
| | - Jacek Małyszko
- 1st Department of Nephrology and Transplantology, Medical University of Bialystok, Bialystok, Poland
| | - Jolanta Małyszko
- Department of Nephrology, Dialysis and Internal Medicine, Medical University of Warsaw, Bialystok, Poland
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Chen YY, Chen XG, Zhang S. Druggability of lipid metabolism modulation against renal fibrosis. Acta Pharmacol Sin 2022; 43:505-519. [PMID: 33990764 PMCID: PMC8888625 DOI: 10.1038/s41401-021-00660-1] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 03/16/2021] [Indexed: 02/08/2023]
Abstract
Renal fibrosis contributes to progressive damage to renal structure and function. It is a common pathological process as chronic kidney disease develops into kidney failure, irrespective of diverse etiologies, and eventually leads to death. However, there are no effective drugs for renal fibrosis treatment at present. Lipid aggregation in the kidney and consequent lipotoxicity always accompany chronic kidney disease and fibrosis. Numerous studies have revealed that restoring the defective fatty acid oxidation in the kidney cells can mitigate renal fibrosis. Thus, it is an important strategy to reverse the dysfunctional lipid metabolism in the kidney, by targeting critical regulators of lipid metabolism. In this review, we highlight the potential "druggability" of lipid metabolism to ameliorate renal fibrosis and provide current pre-clinical evidence, exemplified by some representative druggable targets and several other metabolic regulators with anti-renal fibrosis roles. Then, we introduce the preliminary progress of noncoding RNAs as promising anti-renal fibrosis drug targets from the perspective of lipid metabolism. Finally, we discuss the prospects and deficiencies of drug targeting lipid reprogramming in the kidney.
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Affiliation(s)
- Yuan-yuan Chen
- grid.506261.60000 0001 0706 7839State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union medical college, Beijing, 100050 China
| | - Xiao-guang Chen
- grid.506261.60000 0001 0706 7839State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union medical college, Beijing, 100050 China
| | - Sen Zhang
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union medical college, Beijing, 100050, China.
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Trink J, Li R, Palarasah Y, Troyanov S, Andersen TE, Sidelmann JJ, Inman MD, Pizzo SV, Gao B, Krepinsky JC. Activated Alpha 2-Macroglobulin Is a Novel Mediator of Mesangial Cell Profibrotic Signaling in Diabetic Kidney Disease. Biomedicines 2021; 9:biomedicines9091112. [PMID: 34572299 PMCID: PMC8471248 DOI: 10.3390/biomedicines9091112] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 08/06/2021] [Accepted: 08/24/2021] [Indexed: 11/30/2022] Open
Abstract
Diabetic kidney disease (DKD) is caused by the overproduction of extracellular matrix proteins (ECM) by glomerular mesangial cells (MCs). We previously showed that high glucose (HG) induces cell surface translocation of GRP78 (csGRP78), mediating PI3K/Akt activation and downstream ECM production. Activated alpha 2-macroglobulin (α2M*) is a ligand known to initiate this signaling cascade. Importantly, increased α2M was observed in diabetic patients’ serum, saliva, and glomeruli. Primary MCs were used to assess HG responses. The role of α2M* was assessed using siRNA, a neutralizing antibody and inhibitory peptide. Kidneys from type 1 diabetic Akita and CD1 mice and human DKD patients were stained for α2M/α2M*. α2M transcript and protein were significantly increased with HG in vitro and in vivo in diabetic kidneys. A similar increase in α2M* was seen in media and kidneys, where it localized to the mesangium. No appreciable α2M* was seen in normal kidneys. Knockdown or neutralization of α2M/α2M* inhibited HG-induced profibrotic signaling (Akt activation) and matrix/cytokine upregulation (collagen IV, fibronectin, CTGF, and TGFβ1). In patients with established DKD, urinary α2M* and TGFβ1 levels were correlated. These data reveal an important role for α2M* in the pathogenesis of DKD and support further investigation as a potential novel therapeutic target.
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Affiliation(s)
- Jackie Trink
- Division of Nephrology, McMaster University, Hamilton, ON L8N 4A6, Canada; (J.T.); (R.L.); (B.G.)
| | - Renzhong Li
- Division of Nephrology, McMaster University, Hamilton, ON L8N 4A6, Canada; (J.T.); (R.L.); (B.G.)
| | - Yaseelan Palarasah
- Unit for Thrombosis Research, Department of Regional Health Research, University of Southern Denmark, DK-6705 Esbjerg, Denmark; (Y.P.); (J.J.S.)
| | - Stéphan Troyanov
- Department of Medicine, Hôpital du Sacré-Coeur de Montréal, Faculty of Medicine, Université de Montréal, Montreal, QC H4J 1C5, Canada;
| | - Thomas E. Andersen
- Department of Clinical Microbiology, University of Southern Denmark and Odense University Hospital, DK-5230 Odense, Denmark;
| | - Johannes J. Sidelmann
- Unit for Thrombosis Research, Department of Regional Health Research, University of Southern Denmark, DK-6705 Esbjerg, Denmark; (Y.P.); (J.J.S.)
| | - Mark D. Inman
- Firestone Institute for Respiratory Health, Department of Medicine, McMaster University, Hamilton, ON L8N 1Y3, Canada;
| | - Salvatore V. Pizzo
- Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA;
| | - Bo Gao
- Division of Nephrology, McMaster University, Hamilton, ON L8N 4A6, Canada; (J.T.); (R.L.); (B.G.)
| | - Joan C. Krepinsky
- Division of Nephrology, McMaster University, Hamilton, ON L8N 4A6, Canada; (J.T.); (R.L.); (B.G.)
- Correspondence:
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10
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Use of Lipid-Modifying Agents for the Treatment of Glomerular Diseases. J Pers Med 2021; 11:jpm11080820. [PMID: 34442464 PMCID: PMC8401447 DOI: 10.3390/jpm11080820] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 08/17/2021] [Indexed: 01/14/2023] Open
Abstract
Although dyslipidemia is associated with chronic kidney disease (CKD), it is more common in nephrotic syndrome (NS), and guidelines for the management of hyperlipidemia in NS are largely opinion-based. In addition to the role of circulating lipids, an increasing number of studies suggest that intrarenal lipids contribute to the progression of glomerular diseases, indicating that proteinuric kidney diseases may be a form of "fatty kidney disease" and that reducing intracellular lipids could represent a new therapeutic approach to slow the progression of CKD. In this review, we summarize recent progress made in the utilization of lipid-modifying agents to lower renal parenchymal lipid accumulation and to prevent or reduce kidney injury. The agents mentioned in this review are categorized according to their specific targets, but they may also regulate other lipid-relevant pathways.
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11
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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: 54] [Impact Index Per Article: 13.5] [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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Imafuku T, Watanabe H, Satoh T, Matsuzaka T, Inazumi T, Kato H, Tanaka S, Nakamura Y, Nakano T, Tokumaru K, Maeda H, Mukunoki A, Takeo T, Nakagata N, Tanaka M, Matsushita K, Tsuchiya S, Sugimoto Y, Shimano H, Fukagawa M, Maruyama T. Advanced Oxidation Protein Products Contribute to Renal Tubulopathy via Perturbation of Renal Fatty Acids. ACTA ACUST UNITED AC 2020; 1:781-796. [DOI: 10.34067/kid.0000772019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 06/01/2020] [Indexed: 11/27/2022]
Abstract
BackgroundRenal proximal tubulopathy plays a crucial role in kidney disease, but its molecular mechanism is incompletely understood. Because proximal tubular cells consume a lot of energy during reabsorption, the relationship between fatty acids (FAs) and proximal tubulopathy has been attracting attention. The purpose of this study is to investigate the association between change in renal FA composition and tubulopathy.MethodsMice with cisplatin-induced nephrotoxicity were used as a model of AKI and 5/6-nephrectomized mice were used as a model of CKD. Renal FA composition in mice was measured by GC-MS. Human tubular epithelial cells (HK-2 cells) were used for in vitro studies.ResultsIn kidneys of AKI mice, increased stearic acid (C18:0) and decreased palmitic acid (C16:0) were observed, accompanied by increased expression of the long-chain FA elongase Elovl6. Similar results were also obtained in CKD mice. We show that C18:0 has higher tubular toxicity than C16:0 via induction of ER stress. Using adenovirus-expressing Elovl6 or siRNA for Elovl6 in HK-2 cells, we demonstrated that increased Elovl6 expression contributes to tubulopathy via increasing C18:0. Elovl6 knockout suppressed the increased serum creatinine levels, renal ER stress, and inflammation that would usually result after 5/6 nephrectomy. Advanced oxidation protein products (AOPPs), specifically an oxidized albumin, was found to induce Elovl6 via the mTORC1/SREBP1 pathway.ConclusionsAOPPs may contribute to renal tubulopathy via perturbation of renal FAs through induction of Elovl6. The perturbation of renal FAs induced by the AOPPs-Elovl6 system could be a potential target for the treatment of tubulopathy.
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Dorotea D, Koya D, Ha H. Recent Insights Into SREBP as a Direct Mediator of Kidney Fibrosis via Lipid-Independent Pathways. Front Pharmacol 2020; 11:265. [PMID: 32256356 PMCID: PMC7092724 DOI: 10.3389/fphar.2020.00265] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Accepted: 02/24/2020] [Indexed: 12/17/2022] Open
Abstract
Sterol regulatory-element binding proteins (SREBPs) are classical regulators of cellular lipid metabolism in the kidney and other tissues. SREBPs are currently recognized as versatile transcription factors involved in a myriad of cellular processes. Meanwhile, SREBPs have been recognized to mediate lipotoxicity, contributing to the progression of kidney diseases. SREBP1 has been shown to bind to the promoter region of TGFβ, a major pro-fibrotic signaling mechanism in the kidney. Conversely, TGFβ activates SREBP1 transcriptional activity suggesting a positive feedback loop of SREBP1 in TGFβ signaling. Public ChIP-seq data revealed numerous non-lipid transcriptional targets of SREBPs that plausibly play roles in progressive kidney disease and fibrosis. This review provides new insights into SREBP as a mediator of kidney fibrosis via lipid-independent pathways.
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Affiliation(s)
- Debra Dorotea
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, South Korea
| | - Daisuke Koya
- Department of Internal Medicine, Kanazawa Medical University, Ishikawa, Japan
| | - Hunjoo Ha
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, South Korea
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14
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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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15
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The caveolin-1 regulated protein follistatin protects against diabetic kidney disease. Kidney Int 2019; 96:1134-1149. [DOI: 10.1016/j.kint.2019.05.032] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Revised: 05/27/2019] [Accepted: 05/30/2019] [Indexed: 01/30/2023]
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16
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Van Krieken R, Mehta N, Wang T, Zheng M, Li R, Gao B, Ayaub E, Ask K, Paton JC, Paton AW, Austin RC, Krepinsky JC. Cell surface expression of 78-kDa glucose-regulated protein (GRP78) mediates diabetic nephropathy. J Biol Chem 2019; 294:7755-7768. [PMID: 30914477 DOI: 10.1074/jbc.ra118.006939] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 03/22/2019] [Indexed: 01/21/2023] Open
Abstract
The 78-kDa glucose-regulated protein (GRP78) is a well-established endoplasmic reticulum (ER)-resident chaperone that maintains protein homeostasis and regulates the unfolded protein response. Under conditions of ER stress, GRP78 is also expressed at the cell surface and implicated in tumorigenesis, immunity, and cellular signaling events. The role of cell surface-associated GRP78 (csGRP78) in the pathogenesis of diabetic nephropathy has not yet been defined. Here we explored the role of csGRP78 in regulating high glucose (HG)-induced profibrotic AKT Ser/Thr kinase (AKT) signaling and up-regulation of extracellular matrix proteins. Using primary kidney mesangial cells, we show that HG treatment, but not the osmotic control mannitol, induces csGRP78 expression through an ER stress-dependent mechanism. We found that csGRP78, known to be located on the outer membrane leaflet, interacts with the transmembrane protein integrin β1 and activates focal adhesion kinase and downstream PI3K/AKT signaling. Localization of GRP78 at the cell surface and its interaction with integrin β1 were also required for extracellular matrix protein synthesis in response to HG. Surprisingly, both the N and C termini of csGRP78 were necessary for this profibrotic response. Increased localization of GRP78 at the plasma membrane was also found in the glomerular mesangial area of type 1 diabetic mice in two different models (streptozotocin-induced and Akita). In freshly isolated glomeruli from Akita mice, csGRP78 co-localized with the mesangial cell surface marker α8-integrin. In conclusion, our work reveals a role for csGRP78 in HG-induced profibrotic responses in mesangial cells, informing a potential approach to treating diabetic nephropathy.
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Affiliation(s)
- Richard Van Krieken
- From the Division of Nephrology, McMaster University and St. Joseph's Healthcare, Hamilton, Ontario L8N 4A6, Canada
| | - Neel Mehta
- From the Division of Nephrology, McMaster University and St. Joseph's Healthcare, Hamilton, Ontario L8N 4A6, Canada
| | - Tony Wang
- From the Division of Nephrology, McMaster University and St. Joseph's Healthcare, Hamilton, Ontario L8N 4A6, Canada
| | - Mengyu Zheng
- From the Division of Nephrology, McMaster University and St. Joseph's Healthcare, Hamilton, Ontario L8N 4A6, Canada
| | - Renzhong Li
- From the Division of Nephrology, McMaster University and St. Joseph's Healthcare, Hamilton, Ontario L8N 4A6, Canada
| | - Bo Gao
- From the Division of Nephrology, McMaster University and St. Joseph's Healthcare, Hamilton, Ontario L8N 4A6, Canada
| | - Ehab Ayaub
- the Department of Medicine, Firestone Institute for Respiratory Health, McMaster University and The Research Institute of St. Joe's Hospital, Hamilton, Ontario L8N 4A6, Canada.,the Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario L8S 4L8, Canada, and
| | - Kjetil Ask
- the Department of Medicine, Firestone Institute for Respiratory Health, McMaster University and The Research Institute of St. Joe's Hospital, Hamilton, Ontario L8N 4A6, Canada.,the Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario L8S 4L8, Canada, and
| | - James C Paton
- the Research Centre for Infectious Diseases, Department of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia SA 5005, Australia
| | - Adrienne W Paton
- the Research Centre for Infectious Diseases, Department of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia SA 5005, Australia
| | - Richard C Austin
- From the Division of Nephrology, McMaster University and St. Joseph's Healthcare, Hamilton, Ontario L8N 4A6, Canada
| | - Joan C Krepinsky
- From the Division of Nephrology, McMaster University and St. Joseph's Healthcare, Hamilton, Ontario L8N 4A6, Canada,
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Woodruff TK. Endocrinology-It Takes All of Us. Endocrinology 2018; 159:1873-1874. [PMID: 29718328 DOI: 10.1210/en.2018-00229] [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: 11/19/2022]
Affiliation(s)
- Teresa K Woodruff
- Department of Obstetrics and Gynecology, Northwestern University, Chicago, Illinois
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