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Lin Y, Yang Q, Zeng R. Crosstalk between macrophages and adjacent cells in AKI to CKD transition. Ren Fail 2025; 47:2478482. [PMID: 40110623 PMCID: PMC11926904 DOI: 10.1080/0886022x.2025.2478482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 02/17/2025] [Accepted: 03/07/2025] [Indexed: 03/22/2025] Open
Abstract
Acute kidney injury (AKI), triggered by ischemia, sepsis, toxicity, or obstruction, is marked by a rapid impairment of renal function and could lead to the initiation and advancement of chronic kidney disease (CKD). The concept of AKI to CKD transition has gained much interest. Despite a series of studies highlighting the diverse roles of renal macrophages in the immune response following AKI, the intricate mechanisms of macrophage-driven cell-cell communication in AKI to CKD transition remains incompletely understood. In this review, we introduce the dynamic phenotype change of macrophages under the different stages of kidney injury. Importantly, we present novel perspectives on the extensive interaction of renal macrophages with adjacent cells, including tubular epithelial cells, vascular endothelial cells, fibroblasts, and other immune cells via soluble factors, extracellular vesicles, and direct contact, to facilitate the transition from AKI to CKD. Additionally, we summarize the potential therapeutic strategies based on the adverse macrophage-neighboring cell crosstalk.
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Affiliation(s)
- Yanping Lin
- Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qian Yang
- Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Rui Zeng
- Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Tan Y, Wang X, Zhang D, Wang J, Wang S, Yu J, Wu H. Determining IFI44 as a key lupus nephritis's biomarker through bioinformatics and immunohistochemistry. Ren Fail 2025; 47:2479575. [PMID: 40101924 PMCID: PMC11921169 DOI: 10.1080/0886022x.2025.2479575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Revised: 02/27/2025] [Accepted: 03/06/2025] [Indexed: 03/20/2025] Open
Abstract
BACKGROUND Lupus nephritis (LN) emerges as a severe complication of systemic lupus erythematosus (SLE), significantly affecting patient survival. Despite improvements in treatment reducing LN's morbidity and mortality, existing therapies remain suboptimal, emphasizing the necessity for early detection to improve patient outcomes. METHODS This study employs bioinformatics and machine learning to identify and validate potential LN biomarkers using immunohistochemistry (IHC). It explores the relationship between these biomarkers and the clinical and pathological characteristics of LN, assessing their prognostic significance. The research provides deeper mechanistic insights by employing Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Additionally, the study characterizes the immune profiles of LN patients through the CIBERSORT algorithm, focusing on the role of interferon-inducible protein 44 (IFI44) as a key biomarker. RESULTS IFI44 shows elevated expression in LN-affected kidneys, compared to healthy controls. The levels of IFI44 positively correlate with serum creatinine and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and inversely with serum complement C3 and initial estimated glomerular filtration rate (eGFR). CONCLUSION IFI44 is identified as a promising biomarker for LN, offering potential to refine the assessment of disease progression and predict clinical outcomes. This facilitates the development of more personalized treatment strategies for LN patients.
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Affiliation(s)
- Yue Tan
- Department of Nephrology, The First Hospital of Jilin University, Changchun, China
| | - Xueyao Wang
- Department of Nephrology, The First Hospital of Jilin University, Changchun, China
| | - Deyou Zhang
- Department of Critical Care Medicine, The First Hospital of Jilin University, Changchun, China
| | - Jiahui Wang
- Department of Nephrology, The First Hospital of Jilin University, Changchun, China
| | - Shuxian Wang
- Department of Nephrology, The First Hospital of Jilin University, Changchun, China
| | - Jinyu Yu
- Department of Renal Pathology, The First Hospital of Jilin University, Changchun, China
| | - Hao Wu
- Department of Nephrology, The First Hospital of Jilin University, Changchun, China
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Gao X, Liu X, Han Z, Liao H, Li R. Friend or foe? The role of SIRT6 on macrophage polarized to M2 subtype in acute kidney injury to chronic kidney disease. Ren Fail 2025; 47:2482121. [PMID: 40260529 PMCID: PMC12016254 DOI: 10.1080/0886022x.2025.2482121] [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: 10/30/2024] [Revised: 02/28/2025] [Accepted: 03/14/2025] [Indexed: 04/23/2025] Open
Abstract
Acute kidney injury (AKI) substantially increases the risk of developing and worsening chronic kidney disease (CKD). The shift from AKI to CKD is a complex process that involves various cell types, with macrophages playing a key role in responding to renal injury. M1 and M2 macrophages-the two main types of macrophages-have distinct functions at various stages. M1 macrophages induce kidney damage by secreting pro-inflammatory cytokines immediately after injury, whereas M2 macrophages subsequently facilitate kidney tissue repair. The conversion of macrophages from the M1 to M2 subtype is vital for effective repair after renal injury. However, when M2 macrophages infiltrate persistently, they can paradoxically cause fibrosis, thereby complicating recovery. As a key epigenetic regulatory factor, the deacetylase SIRT6 exerts various biological effects through its enzymatic reactions, including the regulation of cellular metabolism, antioxidant stress response, and inhibition of fibrosis. SIRT6 is expressed in all major types of renal resident cells and is demonstrated to protect the kidneys. SIRT6 promotes the transition from the M1 to M2 subtype; nevertheless, this process poses the risk of fibrosis if macrophages remain in the M2 subtype because of the influence of SIRT6. This review aimed (i) to delve into the intricate role of SIRT6 in macrophage polarization toward the M2 subtype in the context of the progression from AKI to CKD and (ii) to explore potential strategies that may effectively target and mitigate the progression from AKI to CKD.
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Affiliation(s)
- Xiaoqin Gao
- Department of Nephrology, Fifth Hospital of Shanxi Medical University (Shanxi Provincial People’s Hospital), Taiyuan, China
- Department of Nephrology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
| | - Xingwei Liu
- Department of Nephrology, Fifth Hospital of Shanxi Medical University (Shanxi Provincial People’s Hospital), Taiyuan, China
| | - Zhaodi Han
- Drug Clinical Trial Institution, Fifth Hospital of Shanxi Medical University (Shanxi Provincial People’s Hospital), Taiyuan, China
| | - Hui Liao
- Drug Clinical Trial Institution, Fifth Hospital of Shanxi Medical University (Shanxi Provincial People’s Hospital), Taiyuan, China
| | - Rongshan Li
- Department of Nephrology, Fifth Hospital of Shanxi Medical University (Shanxi Provincial People’s Hospital), Taiyuan, China
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Lv R, Liu Z, Guo H, Zhang B, Wang X, Peng Y, Chang Y, Yang F, Xiong Y, Hao J, Gao X, Wang X, Xu Q, Shimosawa T, Qiang P. Fibroblast to macrophage-like cell transition in renal inflammatory injury through the MR/CSF1 pathway induced by aldosterone. Life Sci 2025; 372:123627. [PMID: 40216224 DOI: 10.1016/j.lfs.2025.123627] [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: 01/27/2025] [Revised: 03/25/2025] [Accepted: 04/06/2025] [Indexed: 04/17/2025]
Abstract
AIMS Inflammatory injury promotes the chronic kidney disease (CKD) progression,with renal macrophage accumulation and proliferation of as typical manifestations of inflammatory injury. We aimed to verify fibroblast to macrophage-like cell transition as a new source of macrophages that participate in renal inflammatory injury. MATERIALS AND METHODS Wistar rats were divided into Sham, ALD (aldosterone infusion for 12 weeks), and ESA (aldosterone infusion and esaxerenone by diet for 12 weeks) groups. Rat kidney interstitial fibroblast (RKF) were cultured, induced with aldosterone or CSF1, and treated with antagonists in vitro. The proportions of FSP-1+ F4/80+ cells in the rat kidney and RKF, including M1 marker iNOS/CD86 and M2 marker CD206/CD163 were assessed by flow cytometry and immunofluorescence staining. Single-cell RNA sequencing was used to assess the origin of macrophages in the rat kidneys and related gene expression. Additionally, immunofluorescence was used to detect FSP-1+ F4/80+ cells in kidney biopsy samples from CKD patients. KEY FINDINGS Fibroblast to macrophage-like cell transition was observed in both the kidneys of aldosterone-infused rats and in vitro aldosterone-treated RKF, with a predominant differentiation into the M1 phenotype. This transformation was mediated through the MR/CSF1 signalling pathway, revealing a novel source of macrophages and providing significant insights into the mechanisms underlying organ fibrosis. SIGNIFICANCE Aldosterone induces fibroblast to macrophage-like cell transition through the MR/ CSF1 pathway.
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Affiliation(s)
- Ruyan Lv
- Hebei University of Chinese Medicine, Shijiazhuang 050200, China; Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang 050200, China
| | - Ziqian Liu
- Hebei University of Chinese Medicine, Shijiazhuang 050200, China; Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang 050200, China
| | - Haixia Guo
- Hebei University of Chinese Medicine, Shijiazhuang 050200, China; Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang 050200, China
| | - Boya Zhang
- Hebei University of Chinese Medicine, Shijiazhuang 050200, China; Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang 050200, China
| | - Xuan Wang
- Hebei University of Chinese Medicine, Shijiazhuang 050200, China; Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang 050200, China
| | - Yunsong Peng
- Shijiazhuang Hospital of Traditional Chinese Medicine, Shijiazhuang 050200, China
| | - Yi Chang
- Hebei University of Chinese Medicine, Shijiazhuang 050200, China; Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang 050200, China; Institute of Integrative Medicine, College of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang 050200, China
| | - Fan Yang
- Hebei University of Chinese Medicine, Shijiazhuang 050200, China; Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang 050200, China; Institute of Integrative Medicine, College of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang 050200, China
| | - Yunzhao Xiong
- Hebei University of Chinese Medicine, Shijiazhuang 050200, China; Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang 050200, China; Institute of Integrative Medicine, College of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang 050200, China
| | - Juan Hao
- Shijiazhuang Hospital of Traditional Chinese Medicine, Shijiazhuang 050200, China
| | - Xiaomeng Gao
- Hebei University of Chinese Medicine, Shijiazhuang 050200, China; Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang 050200, China
| | - Xiangting Wang
- Hebei University of Chinese Medicine, Shijiazhuang 050200, China; Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang 050200, China; Institute of Integrative Medicine, College of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang 050200, China
| | - Qingyou Xu
- Hebei University of Chinese Medicine, Shijiazhuang 050200, China; Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang 050200, China; Institute of Integrative Medicine, College of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang 050200, China.
| | - Tatsuo Shimosawa
- Department of Clinical Laboratory, School of Medicine, International University of Health and Welfare, Narita 286-8686, Japan.
| | - Panpan Qiang
- Hebei University of Chinese Medicine, Shijiazhuang 050200, China; Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang 050200, China; Institute of Integrative Medicine, College of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang 050200, China.
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Gao Z. New insights into Smad3 in cardiac fibrosis. Gene 2025; 952:149418. [PMID: 40089084 DOI: 10.1016/j.gene.2025.149418] [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: 01/26/2025] [Revised: 03/04/2025] [Accepted: 03/13/2025] [Indexed: 03/17/2025]
Abstract
Damage to myocardial tissues, leading to myocardial fibrosis, is a significant pathological hallmark across various heart diseases. SMAD3, a central transcriptional regulator within the transforming growth factor-beta (TGF-β) signaling pathway, plays a pivotal role in the pathological progression of myocardial fibrosis and cardiac remodeling. It intricately regulates physiological and pathological processes encompassing cell proliferation, differentiation, tissue repair, and fibrosis. Notably, SMAD3 exerts crucial influences in myocardial fibrosis subsequent to myocardial infarction, pressure overload-induced myocardial fibrosis, diabetic cardiomyopathy (DCM), aging-associated cardiac fibrosis and myocarditis-related myocardial fibrosis. The targeted modulation of genes or the utilization of compounds, including traditional Chinese medicine (paeoniflorin, baicalin, and genistein et al.) and other pharmaceutical agents that modulate SMAD3, may offer avenues for restraining the pathological cascade of myocardial fibrosis. Consequently, targeted regulation of SMAD3 associated with myocardial fibrosis may herald novel therapeutic paradigms for ameliorating myocardial diseases.
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Affiliation(s)
- Zhen Gao
- Liaocheng Vocational and Technical College, Shandong, China.
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6
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Boiko JR, Hill GR. Chronic Graft-versus-host Disease: Immune Insights, Therapeutic Advances, and Parallels for Solid Organ Transplantation. Transplantation 2025; 109:955-966. [PMID: 39682018 PMCID: PMC12097962 DOI: 10.1097/tp.0000000000005298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2024]
Abstract
Chronic graft-versus-host disease (cGVHD) remains a frequent and morbid outcome of allogeneic hematopoietic cell transplantation (HCT), in which the donor-derived immune system attacks healthy recipient tissue. Preceding tissue damage mediated by chemoradiotherapy and alloreactive T cells compromise central and peripheral tolerance mechanisms, leading to aberrant donor T cell and germinal center B cell differentiation, culminating in pathogenic macrophage infiltration and differentiation in target tissue, with ensuant fibrosis. This process results in a heterogeneous clinical syndrome with significant morbidity and mortality, frequently requiring prolonged therapy. In this review, we discuss the processes that interrupt immune tolerance, the subsequent clinical manifestations, and new FDA-approved therapeutic approaches that have been born from a greater understanding of disease pathogenesis in preclinical systems, linking to parallel processes following solid organ transplantation.
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Affiliation(s)
- Julie R. Boiko
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA
- Department of Pediatrics, University of Washington, Seattle, WA
| | - Geoffrey R. Hill
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA
- Department of Medicine, University of Washington, Seattle, WA
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7
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Liang W, Wu H, Long Q, Lin H, Lv X, Ma W, Wu T, Li A, Zheng Q, Guo J, Chen X, Guo J, Sun D. LKB1 activated by NaB inhibits the IL-4/STAT6 axis and ameliorates renal fibrosis through the suppression of M2 macrophage polarization. Life Sci 2025; 370:123564. [PMID: 40097066 DOI: 10.1016/j.lfs.2025.123564] [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: 12/07/2024] [Revised: 03/03/2025] [Accepted: 03/13/2025] [Indexed: 03/19/2025]
Abstract
BACKGROUND Renal fibrosis is a critical pathological characteristic of chronic kidney disease, and current antifibrotic therapies has limited efficacy. Sodium butyrate (NaB) has been shown to be highly effective in mitigating bleomycin-induced pulmonary fibrosis; however, its specific impact on renal fibrosis and the underlying mechanisms remain unclear. This study aims to elucidate the role and mechanism of NaB in renal fibrosis by using a mouse model of renal fibrosis induced through Unilateral Ureteral Obstruction (UUO) and folic acid (FA) administration. RESULTS NaB significantly decreased the distribution of collagen fibers in renal tissues and mitigated fibrosis in a dose-dependent manner. Further analysis indicated that NaB inhibited M2 macrophage polarization in the renal tissues of UUO model mice by blocking the phosphorylation of STAT6, hence reducing renal fibrosis. Additionally, in vitro experiments demonstrated that NaB inhibited fibroblast activation induced by M2 macrophages. Mechanistic studies revealed that NaB attenuates fibroblast activation and M2 macrophage polarization by upregulating LKB1 and inhibiting the activation of the STAT6 signaling pathway. CONCLUSION NaB may exert its effects by inhibiting the activation of the IL-4/STAT6 signaling pathway through the upregulation of LKB1, which suppress the polarization of M2 macrophages and consequently reduce renal fibrosis. These findings establish a theoretical foundation for NaB as a novel drug candidate for renal fibrosis and indicate its potential applicability in clinical treatments for this condition.
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Affiliation(s)
- Weifei Liang
- Department of Urology, Shenzhen Hospital, Southern Medical University, Shenzhen 518100, China; Center for Cancer and Immunology Research, State Key Laboratory of Respiratory Disease, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, 510180 Guangzhou, Guangdong, China
| | - Haoyu Wu
- School of Public Health, Wenzhou Medical University, Wenzhou 325035, China; South Zhejiang Institute of Radiation Medicine and Nuclear Technology Application, Wenzhou 325809, China; Zhejiang Provincial Key Laboratory of Watershed Sciences and Health, Wenzhou Medical University, Wenzhou 325035, China
| | - Qishan Long
- Department of Urology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong, China
| | - Hong Lin
- Department of Laboratory Medicine, Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan People's Hospital, 511518 Qingyuan, Guangdong, China
| | - Xiaoyu Lv
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, 138 Yixueyuan Road, Xuhui District, Shanghai 200032, China
| | - Wen Ma
- Clinical Laboratory, Shenzhen Hospital, Southern Medical University, Shenzhen 518100, China
| | - Tao Wu
- Department of Urology, Shenzhen Hospital, Southern Medical University, Shenzhen 518100, China
| | - Ai Li
- Department of Clinical Medicine, The Second Clinical School of Guangzhou Medical University, Guangzhou 510000, China
| | - Qingyou Zheng
- Department of Urology, Shenzhen Hospital, Southern Medical University, Shenzhen 518100, China
| | - Jinan Guo
- Department of Urology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong, China.
| | - Xiangqiu Chen
- Department of Urology, Shenzhen Hospital, Southern Medical University, Shenzhen 518100, China.
| | - Jing Guo
- Center of Oncology, Heyou Hospital, Shunde District, Foshan City 528306, Address:No. 1 of Heren Road, Junlan Community, Beijiao Town, Shunde District, Foshan City, Guangdong Province, China.
| | - Donglin Sun
- Department of Urology, Shenzhen Hospital, Southern Medical University, Shenzhen 518100, China.
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8
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Guo H, Liu Z, Lv R, Zhang B, Qiang P, Wang X, Chang Y, Yang F, Shimosawa T, Xu Q, Xiong Y. Aldosterone induces renal lymphangiogenesis through macrophage-lymphatic endothelial cell transformation and Inhibition by esaxerenone. Inflamm Res 2025; 74:85. [PMID: 40413281 DOI: 10.1007/s00011-025-02044-1] [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: 02/03/2025] [Revised: 04/18/2025] [Accepted: 04/25/2025] [Indexed: 05/27/2025] Open
Abstract
OBJECTIVE AND DESIGN Inflammation plays a crucial role in the occurrence and development of renal fibrosis. Lymphatic vessels have emerged as new hotspots in the domain of inflammation. Recent studies have revealed that macrophages are involved in lymphangiogenesis through direct and indirect mechanisms. However, the underlying mechanisms of macrophage transdifferentiation into lymphatic endothelial cells (LECs) are still poorly understood. METHODS In vivo, thirty male Wistar rats were randomly divided into a sham group, an aldosterone group and an aldosterone + esaxerenone group. In vitro, Raw 264.7 cells and bone marrow-derived macrophages (BMDMs) were used. H&E, Masson, western blotting, immunohistochemistry, immunofluorescence, flow cytometry, and BMDM tube formation assays were used to assess renal fibrosis and lymphangiogenesis in a rat model of aldosterone-induced renal injury. RESULTS In this study, we observed pathological renal fibrosis and lymphangiogenesis in 12-week-old rats after aldosterone infusion. In addition, the treatment of rats with esaxerenone, a mineralocorticoid receptor blocker (MRB), significantly reduced renal lymphangiogenesis and fibrosis. Interestingly, we found that aldosterone can activate MR to stimulate macrophages to secrete vascular endothelial growth factor C (VEGF-C) and promote lymphatic angiogenesis. CONCLUSIONS Our data suggest that renal fibrosis occurs in aldosterone-treated rats and that inflammation-induced macrophage transdifferentiation into LECs occurs during this process and that MRB attenuates renal fibrosis and lymphangiogenesis due to inflammatory injury.
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Affiliation(s)
- Haixia Guo
- Graduate School, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China
- Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China
| | - Ziqian Liu
- Graduate School, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China
- Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China
| | - Ruyan Lv
- Graduate School, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China
- Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China
| | - Boya Zhang
- Graduate School, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China
- Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China
| | - Panpan Qiang
- Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China
- Institute of Integrative Medicine, College of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, China
| | - Xuan Wang
- Graduate School, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China
- Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China
- Institute of Integrative Medicine, College of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, China
| | - Yi Chang
- Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China
- Institute of Integrative Medicine, College of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, China
| | - Fan Yang
- Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China
- Institute of Integrative Medicine, College of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, China
| | - Tatsuo Shimosawa
- Department of Clinical Laboratory, School of Medicine, International University of Health and Welfare, Narita, 286-8686, Japan
| | - Qingyou Xu
- Graduate School, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China.
- Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China.
- Institute of Integrative Medicine, College of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, China.
- Department of Internal Medicine, Hebei University of Chinese Medicine, 326 Xinshinan Road, Shijiazhuang, 050091, China.
| | - Yunzhao Xiong
- Graduate School, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China.
- Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China.
- Institute of Integrative Medicine, College of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, China.
- Department of Internal Medicine, Hebei University of Chinese Medicine, 326 Xinshinan Road, Shijiazhuang, 050091, China.
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9
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Li Y, Xue L, Feng J, Wang Z, Long Y, Liu W, Zhang S, Zhi X, Hao H, Wang X, Liu H, Wang L. Insufficient BK channel function enhances NF-κB nuclear translocation and promotes IL-6 synthesis in vascular smooth muscle cells induced by AT1-AA. Biochem Pharmacol 2025:117000. [PMID: 40414513 DOI: 10.1016/j.bcp.2025.117000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 04/06/2025] [Accepted: 05/22/2025] [Indexed: 05/27/2025]
Abstract
The inflammatory phenotype of vascular smooth muscle cells (VSMCs) is an important factor in triggering vascular disease, and interleukin-6 (IL-6) is one of the earliest inflammatory cytokines upregulated in many inflammatory contexts. Angiotensin II-1 receptor autoantibody (AT1-AA) can promote the phenotypic transformation of VSMCs into macrophage-like cells, then synthesize abundant IL-6 to induce vascular inflammation. Previous studies suggested that abnormal BK channel function on the surface of VSMCs played an important role in the synthesis of IL-6, but the mechanism of abnormal BK channel involvement in AT1-AA-induced IL-6 synthesis in VSMCs was unclear. In this study, the agonist NS1619 of the BK channel and the inhibitor Paxilline were used to reverse or exacerbate IL-6 synthesis in AT1-AA-induced VSMCs. It is known that NF-κB can enter the nucleus due to increased calcium ion concentration caused by BK channel dysfunction, thereby increasing IL-6 transcription. This study observed that Paxilline pretreatment significantly increased the residence time of AT1-AA-induced NF-κB in the nucleus, while NS1619 pretreatment showed the opposite trend. JSH-23 inhibiting NF-κB nuclear entry reversed the increase in IL-6 expression in VSMCs induced by AT1-AA. This study found that AT1-AA enhanced NF-κB nuclear translocation by inhibiting BK channel function, which in turn promoted IL-6 transcription in VSMCs, increased IL-6 synthesis, and induced vascular inflammation. This study revealed the importance of BK channel dysfunction in the process of AT1-AA increasing IL-6 synthesis and promoting vascular inflammation, and provided a new idea for alleviating vascular inflammatory diseases from the perspective of improving potassium channel function.
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Affiliation(s)
- Yang Li
- School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, PR China
| | - Lingxia Xue
- School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, PR China
| | - Jiayan Feng
- School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, PR China
| | - Zhuoxi Wang
- School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, PR China
| | - Yaolin Long
- School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, PR China
| | - Weiqian Liu
- School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, PR China
| | - Suli Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, PR China
| | - Xiaoyan Zhi
- School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, PR China
| | - Haihu Hao
- Department of Orthopaedics, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, PR China
| | - Xiaohui Wang
- School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, PR China
| | - Huirong Liu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, PR China
| | - Li Wang
- School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, PR China.
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10
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Chen X, Wu C, Tang F, Zhou J, Mo L, Li Y, He J. The Immune Microenvironment: New Therapeutic Implications in Organ Fibrosis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e05067. [PMID: 40391706 DOI: 10.1002/advs.202505067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/20/2025] [Revised: 04/28/2025] [Indexed: 05/22/2025]
Abstract
Fibrosis, characterized by abnormal deposition of structural proteins, is a major cause of tissue dysfunction in chronic diseases. The disease burden associated with progressive fibrosis is substantial, and currently approved drugs are unable to effectively reverse it. Immune cells are increasingly recognized as crucial regulators in the pathological process of fibrosis by releasing effector molecules, such as cytokines, chemokines, extracellular vesicles, metabolites, proteases, or intercellular contact. Therefore, targeting the immune microenvironment can be a potential strategy for fibrosis reduction and reversion. This review summarizes the recent advances in the understanding of the immune microenvironment in fibrosis including phenotypic and functional transformations of immune cells and the interaction of immune cells with other cells. The novel opportunities for the discovery and development of drugs for immune microenvironment remodeling and their associated challenges are also discussed.
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Affiliation(s)
- Xiangqi Chen
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Chuan Wu
- State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Fei Tang
- State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jingyue Zhou
- State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Li Mo
- Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yanping Li
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jinhan He
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
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11
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Zhao Y, Zhu XY, Ma W, Zhang Y, Yuan F, Kim SR, Tang H, Jordan K, Lerman A, Tchkonia T, Kirkland JL, Lerman LO. Cellular senescence promotes macrophage-to-myofibroblast transition in chronic ischemic renal disease. Cell Death Dis 2025; 16:372. [PMID: 40348745 PMCID: PMC12065848 DOI: 10.1038/s41419-025-07666-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 04/07/2025] [Accepted: 04/14/2025] [Indexed: 05/14/2025]
Abstract
Cellular senescence participates in the pathophysiology of post-stenotic kidney damage, but how it regulates tissue remodeling is incompletely understood. Macrophage-myofibroblast transition (MMT) contributes to the development of tissue fibrosis. We hypothesized that cellular senescence contributes to MMT and renal fibrosis in mice with renal artery stenosis (RAS). INK-ATTAC mice expressing p16INK-4a and green fluorescent protein in senescent cells were assigned to control or unilateral RAS, untreated or treated with AP20187 (an apoptosis inducer in p16INK-4a-expressing cells) for 4 weeks. Renal perfusion was studied in vivo using micro-MRI, and kidney morphology, senescence, and MMT ex vivo. Cellular senescence was induced in human renal proximal tubular epithelial cells (HRPTEpiC) in vitro, and interferon-induced transmembrane protein-3 (IFITM3), a cellular senescence vector, was silenced (siRNA) or over-expressed (plasmid). HRPTEpiC were then co-incubated with macrophages with silenced integrin-3 (ITGB3), a regulator of mesenchymal transitions. CD68/p16INK-4a/α-SMA co-expression and senescence markers were studied. Murine RAS kidneys showed increased expression of p16INK-4a and MMT markers (F4/80, α-SMA) vs. controls, which decreased after AP20187, as did renal fibrosis and plasma creatinine, whereas renal perfusion increased. IFITM3 and ITGB3 expression were upregulated in senescent HRPTEpiC or co-cultured macrophages, respectively. MMT markers and TGF-β/Smad3 expression also rose in these macrophages and decreased after IFITM3 or ITGB3 silencing. p16INK-4a-expressing macrophages may regulate interstitial fibrosis in RAS via MMT. This process is associated with elevated expression of ITGB3 and TGF-β/Smad3 pathway activation through neighboring senescent cell-derived IFITM3. These findings may implicate MMT as a therapeutic target in ischemic kidneys.
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Affiliation(s)
- Yu Zhao
- Institute of Nephrology, Zhong Da Hospital, Southeast University, School of Medicine, Nanjing, Jiangsu, PR China
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
| | - Xiang-Yang Zhu
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
| | - Wenqi Ma
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Ying Zhang
- Institute of Nephrology, Zhong Da Hospital, Southeast University, School of Medicine, Nanjing, Jiangsu, PR China
| | - Fei Yuan
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
- Department of Urology, National Children's Medical Center, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, PR China
| | - Seo Rin Kim
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
| | - Hui Tang
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
| | - Kyra Jordan
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
| | - Amir Lerman
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA
| | - Tamara Tchkonia
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
| | - James L Kirkland
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
- Division of General Internal Medicine, Mayo Clinic, Rochester, MN, USA
| | - Lilach O Lerman
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA.
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Zhang D, Zhang YH, Liu B, Yang HX, Li GT, Zhou HL, Wang YS. Role of peroxisomes in the pathogenesis and therapy of renal fibrosis. Metabolism 2025; 166:156173. [PMID: 39993498 DOI: 10.1016/j.metabol.2025.156173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Revised: 02/18/2025] [Accepted: 02/20/2025] [Indexed: 02/26/2025]
Abstract
Renal fibrosis is a pathological consequence of end-stage chronic kidney disease, driven by factors such as oxidative stress, dysregulated fatty acid metabolism, extracellular matrix (ECM) imbalance, and epithelial-to-mesenchymal transition. Peroxisomes play a critical role in fatty acid β-oxidation and the scavenging of reactive oxygen species, interacting closely with mitochondrial functions. Nonetheless, current research often prioritizes the mitochondrial influence on renal fibrosis, often overlooking the contribution of peroxisomes. This comprehensive review systematically elucidates the fundamental biological functions of peroxisomes and delineates the molecular mechanisms underlying peroxisomal dysfunction in renal fibrosis pathogenesis. Here, we discuss the impact of peroxisome dysfunction and pexophagy on oxidative stress, ECM deposition, and renal fibrosis in various cell types including mesangial cells, endothelial cells, podocytes, epithelial cells, and macrophages. Furthermore, this review highlights the recent advancements in peroxisome-targeted therapeutic strategies to alleviate renal fibrosis.
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Affiliation(s)
- Dan Zhang
- Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun 130021, China
| | - Yang-He Zhang
- Department of Urology, The First Hospital of Jilin University, Changchun 130021, China
| | - Bin Liu
- Department of Urology, The First Hospital of Jilin University, Changchun 130021, China
| | - Hong-Xia Yang
- Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun 130021, China
| | - Guang-Tao Li
- Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun 130021, China
| | - Hong-Lan Zhou
- Department of Urology, The First Hospital of Jilin University, Changchun 130021, China.
| | - Yi-Shu Wang
- Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun 130021, China.
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13
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Li Y, Cai J, Xu Y, Zou Y, Xu S, Zheng X, Fu L, Zhang J, Ma X, He Y, Wang X, Deng K, Guo J. Macrophage-myofibroblast transition contributes to the macrophage elimination and functional regeneration in the late stage of nerve injury. Exp Neurol 2025; 387:115194. [PMID: 39993460 DOI: 10.1016/j.expneurol.2025.115194] [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: 01/17/2025] [Revised: 02/19/2025] [Accepted: 02/20/2025] [Indexed: 02/26/2025]
Abstract
Massive of macrophages are recruited to the injured nerve to remove the axonal and myelin debris for creating a conducive micro-environment for nerve regeneration. However, the fate of macrophages after the debris clearing remains unclear. In this study, we demonstrated that the number of macrophages in the crush injured sciatic nerve of mice peaked at 7 days post injury (dpi) and then decreased significantly in the late stage of nerve injury. Mechanismly, the macrophage elimination was primarily attributed to TGF-β/Smad3 signaling dependent macrophage-myofibroblast transition (MMT), rather than apoptosis or out-migration. Furthermore, MMT caused collagen deposition is conducive to nerve regeneration. Both macrophage depletion via clodronate liposomes and MMT blockade using TGF-β/Smad3 inhibitor significantly reduced collagen deposition and impaired functional nerve regeneration. In summary, the present study indicates that TGF-β/Smad3 regulated MMT contributes to macrophage elimination and functional recovery in the injury nerve.
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Affiliation(s)
- Yunlun Li
- Department of Histology and Embryology, Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, National Demonstration Center for Experimental Education, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong Province, China; Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangzhou, Guangdong Province, China
| | - Jiale Cai
- Department of Histology and Embryology, Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, National Demonstration Center for Experimental Education, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong Province, China; Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangzhou, Guangdong Province, China
| | - Yizhou Xu
- Department of Histology and Embryology, Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, National Demonstration Center for Experimental Education, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong Province, China; Department of Spine Orthopedics, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Ying Zou
- Department of Histology and Embryology, Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, National Demonstration Center for Experimental Education, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Shuyi Xu
- Department of Histology and Embryology, Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, National Demonstration Center for Experimental Education, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong Province, China; Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangzhou, Guangdong Province, China
| | - Xinya Zheng
- Department of Histology and Embryology, Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, National Demonstration Center for Experimental Education, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Lanya Fu
- Department of Histology and Embryology, Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, National Demonstration Center for Experimental Education, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Jiaqi Zhang
- Department of Histology and Embryology, Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, National Demonstration Center for Experimental Education, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Xinrui Ma
- Department of Histology and Embryology, Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, National Demonstration Center for Experimental Education, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Ye He
- Department of Histology and Embryology, Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, National Demonstration Center for Experimental Education, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Xianghai Wang
- Department of Histology and Embryology, Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, National Demonstration Center for Experimental Education, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong Province, China; Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangzhou, Guangdong Province, China
| | - Kaixian Deng
- Department of Gynecology, Shunde Hospital of Southern Medical University, Foshan, China
| | - Jiasong Guo
- Department of Histology and Embryology, Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, National Demonstration Center for Experimental Education, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong Province, China; Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangzhou, Guangdong Province, China.
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14
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Wang H, Ding K, He J, Wang J. Tetrahydropalmatine promotes macrophage autophagy by inhibiting the AMPK/mTOR pathway to attenuate atherosclerosis. Histol Histopathol 2025; 40:697-710. [PMID: 39359170 DOI: 10.14670/hh-18-809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/04/2024]
Abstract
BACKGROUND Atherosclerosis (AS) is a chronic progressive arterial disease that is associated with macrophage autophagy and AMP-activated protein kinase (AMPK)/mechanistic target of the rapamycin (mTOR) pathway. Tetrahydropalmatine (THP) can activate AMPK-dependent autophagy. We aim to study the mechanism of macrophage autophagy mediated by THP in the treatment of AS via the AMPK/mTOR pathway. METHODS High-fat diet apolipoprotein E-deficient mice and ox-LDL-induced RAW264.7 cells were used to mimic the AS model, then THP was administered. Cell viability was detected by MTT. Pathological aorta lesions were detected using Hematoxylin and Eosin, Masson, and oil red staining. Lipid metabolism indices and inflammatory factors were measured using ELISA. A transmission electron microscope was used to observe autophagosomes. Autophagy and AMPK/mTOR pathway protein expression was detected by immunofluorescence and Western blot. The AMPK inhibitor 9-β-d-Arabinofuranosyl Adenine (Ara-A) was used to validate the effect of THP. The mRNA expression of Beclin-1 and MCP-1 was detected by q-PCR. RESULTS THP administration regulated lipid metabolism by lowering total cholesterol, triacylglycerol, low-density lipoprotein, and high-density lipoprotein levels, and suppressed aortic damage. THP suppressed aortic damage and regulated lipid metabolism by altering serum lipid levels. THP reduced inflammation and macrophage CD68 expression. Twenty μg/mL THP reduced cell viability. THP decreased cholesterol uptake and increased efflux, promoting autophagy. THP increased autophagosome number, LC3B expression, and autophagy markers p-AMPK/AMPK and LC3-II/LC3-I. THP also decreased p-mTOR/mTOR and P62. THP increased Beclin-1 mRNA expression and decreased MCP-1 mRNA expression. Ara-A reversed THP's effects. CONCLUSION THP promotes macrophage autophagy by inhibiting the AMPK/mTOR pathway to attenuate AS.
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Affiliation(s)
- Hui Wang
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Ke Ding
- Department of Pharmacy, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.
| | - Jiaqi He
- Traditional Chinese Medicine Dispensary, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Jiahong Wang
- Traditional Chinese Medicine Dispensary, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
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15
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Meng XM, Wang L, Nikolic-Paterson DJ, Lan HY. Innate immune cells in acute and chronic kidney disease. Nat Rev Nephrol 2025:10.1038/s41581-025-00958-x. [PMID: 40263532 DOI: 10.1038/s41581-025-00958-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/24/2025] [Indexed: 04/24/2025]
Abstract
Acute kidney injury (AKI) and chronic kidney disease (CKD) are inter-related clinical and pathophysiological disorders. Cells of the innate immune system, such as granulocytes and macrophages, can induce AKI through the secretion of pro-inflammatory mediators such as cytokines, chemokines and enzymes, and the release of extracellular traps. In addition, macrophages and dendritic cells can drive the progression of CKD through a wide range of pro-inflammatory and pro-fibrotic mechanisms, and by regulation of the adaptive immune response. However, innate immune cells can also promote kidney repair after acute injury. These actions highlight the multifaceted nature of the way by which innate immune cells respond to signals within the kidney microenvironment, including interaction with the complement and coagulation cascades, cells of the adaptive immune system, intrinsic renal cells and infiltrating mesenchymal cells. The factors and mechanisms that underpin the ability of innate immune cells to contribute to renal injury or repair and to drive the progression of CKD are of great interest for understanding disease processes and for developing new therapeutic approaches to limit AKI and the AKI-to-CKD transition.
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Affiliation(s)
- Xiao-Ming Meng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, the Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Li Wang
- Research Center of Integrated Traditional Chinese and Western Medicine, the Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, China
| | - David J Nikolic-Paterson
- Department of Nephrology, Monash Medical Centre and Monash University Centre for Inflammatory Diseases, Melbourne, Victoria, Australia
| | - Hui-Yao Lan
- Research Center of Integrated Traditional Chinese and Western Medicine, the Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, China.
- Departments of Medicine & Therapeutics, the Chinese University of Hong Kong, Hong Kong, and Guangdong-Hong Kong Joint Laboratory for Immunological and Genetic Kidney Disease, Guangdong Academy of Medical Science, Guangdong Provincial People's Hospital, Guangzhou, China.
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16
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Huang Z, Li Z, Ruan D, Xu Y, Cai H, Liu H, Jin H, He P, Fei Y, Huang J, Wang C, Chen X, Jiang J, Shen W. Dynamic changes of molecular pattern and cellular subpopulation in puncture-induced tendon injury model. iScience 2025; 28:112034. [PMID: 40230536 PMCID: PMC11994932 DOI: 10.1016/j.isci.2025.112034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 07/03/2024] [Accepted: 02/12/2025] [Indexed: 04/16/2025] Open
Abstract
Tendon degeneration and injury often result in significant pain and functional impairment. Typically, tendon healing occurs through a scar-mediated response and may progress to chronic tendinopathy without timely intervention. However, the molecular mechanisms underlying early tendon repair remain poorly understood. Further investigation is also impeded by the limited availability of early tendon injury samples in clinical settings. In this study, we established a puncture-induced tendon injury model to investigate the molecular patterns and cellular subpopulations involved in early tendon injury across multiple time points. RNA sequencing identified seven gene sets with distinct expression profiles during the early stages of tendon injury. Single-cell RNA sequencing further revealed eight myeloid cell types and seven mesenchymal cell types participating in the tendon repair process. Together, these findings illuminate the molecular and cellular dynamics coordinating early tendon repair, providing insights that could inform future clinical treatments for tendinopathy and tendon injury.
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Affiliation(s)
- Zizhan Huang
- Department of Sports Medicine & Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, P.R. China
- Institute of Sports Medicine, Zhejiang University, Hangzhou City, Zhejiang Province, P.R. China
- Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, P.R. China
- Zhejiang Key Laboratory of Motor System Disease Precision Research and Therapy, Hangzhou City, Zhejiang Province, P.R. China
- Clinical Research Center of Motor System Disease of Hangzhou City, Hangzhou City, Zhejiang Province, P.R. China
| | - Ziyang Li
- Department of Sports Medicine & Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, P.R. China
- Institute of Sports Medicine, Zhejiang University, Hangzhou City, Zhejiang Province, P.R. China
- Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, P.R. China
- Zhejiang Key Laboratory of Motor System Disease Precision Research and Therapy, Hangzhou City, Zhejiang Province, P.R. China
- Clinical Research Center of Motor System Disease of Hangzhou City, Hangzhou City, Zhejiang Province, P.R. China
| | - Dengfeng Ruan
- Department of Sports Medicine & Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, P.R. China
- Institute of Sports Medicine, Zhejiang University, Hangzhou City, Zhejiang Province, P.R. China
- Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, P.R. China
- Zhejiang Key Laboratory of Motor System Disease Precision Research and Therapy, Hangzhou City, Zhejiang Province, P.R. China
- Clinical Research Center of Motor System Disease of Hangzhou City, Hangzhou City, Zhejiang Province, P.R. China
- China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou, China
| | - Yiwen Xu
- Department of Sports Medicine & Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, P.R. China
- Institute of Sports Medicine, Zhejiang University, Hangzhou City, Zhejiang Province, P.R. China
- Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, P.R. China
- Zhejiang Key Laboratory of Motor System Disease Precision Research and Therapy, Hangzhou City, Zhejiang Province, P.R. China
- Clinical Research Center of Motor System Disease of Hangzhou City, Hangzhou City, Zhejiang Province, P.R. China
| | - Honglu Cai
- Department of Sports Medicine & Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, P.R. China
- Institute of Sports Medicine, Zhejiang University, Hangzhou City, Zhejiang Province, P.R. China
- Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, P.R. China
- Zhejiang Key Laboratory of Motor System Disease Precision Research and Therapy, Hangzhou City, Zhejiang Province, P.R. China
- Clinical Research Center of Motor System Disease of Hangzhou City, Hangzhou City, Zhejiang Province, P.R. China
| | - Hengzhi Liu
- Department of Sports Medicine & Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, P.R. China
- Institute of Sports Medicine, Zhejiang University, Hangzhou City, Zhejiang Province, P.R. China
- Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, P.R. China
- Zhejiang Key Laboratory of Motor System Disease Precision Research and Therapy, Hangzhou City, Zhejiang Province, P.R. China
- Clinical Research Center of Motor System Disease of Hangzhou City, Hangzhou City, Zhejiang Province, P.R. China
| | - Haocheng Jin
- Department of Orthopedics, National Center for Orthopedics, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
| | - Peiwen He
- Department of Sports Medicine & Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, P.R. China
- Institute of Sports Medicine, Zhejiang University, Hangzhou City, Zhejiang Province, P.R. China
- Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, P.R. China
- Zhejiang Key Laboratory of Motor System Disease Precision Research and Therapy, Hangzhou City, Zhejiang Province, P.R. China
- Clinical Research Center of Motor System Disease of Hangzhou City, Hangzhou City, Zhejiang Province, P.R. China
| | - Yang Fei
- Department of Sports Medicine & Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, P.R. China
- Institute of Sports Medicine, Zhejiang University, Hangzhou City, Zhejiang Province, P.R. China
- Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, P.R. China
- Zhejiang Key Laboratory of Motor System Disease Precision Research and Therapy, Hangzhou City, Zhejiang Province, P.R. China
- Clinical Research Center of Motor System Disease of Hangzhou City, Hangzhou City, Zhejiang Province, P.R. China
| | - Jiayun Huang
- Department of Sports Medicine & Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, P.R. China
- Institute of Sports Medicine, Zhejiang University, Hangzhou City, Zhejiang Province, P.R. China
- Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, P.R. China
- Zhejiang Key Laboratory of Motor System Disease Precision Research and Therapy, Hangzhou City, Zhejiang Province, P.R. China
- Clinical Research Center of Motor System Disease of Hangzhou City, Hangzhou City, Zhejiang Province, P.R. China
| | - Canlong Wang
- Department of Sports Medicine & Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, P.R. China
- Institute of Sports Medicine, Zhejiang University, Hangzhou City, Zhejiang Province, P.R. China
- Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, P.R. China
- Zhejiang Key Laboratory of Motor System Disease Precision Research and Therapy, Hangzhou City, Zhejiang Province, P.R. China
- Clinical Research Center of Motor System Disease of Hangzhou City, Hangzhou City, Zhejiang Province, P.R. China
| | - Xiao Chen
- Department of Sports Medicine & Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, P.R. China
- Zhejiang Key Laboratory of Motor System Disease Precision Research and Therapy, Hangzhou City, Zhejiang Province, P.R. China
- Dr. Li Dak Sum-Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, P.R. China
- Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou City, P.R. China
- State Key Laboratory of Transvascular Implantation Devices, Hangzhou City, Zhejiang Province, P.R. China
- China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou, China
| | - Jia Jiang
- Department of Orthopedics, National Center for Orthopedics, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
| | - Weiliang Shen
- Department of Sports Medicine & Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, P.R. China
- Institute of Sports Medicine, Zhejiang University, Hangzhou City, Zhejiang Province, P.R. China
- Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, P.R. China
- Zhejiang Key Laboratory of Motor System Disease Precision Research and Therapy, Hangzhou City, Zhejiang Province, P.R. China
- Clinical Research Center of Motor System Disease of Hangzhou City, Hangzhou City, Zhejiang Province, P.R. China
- Dr. Li Dak Sum-Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, P.R. China
- Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou City, P.R. China
- State Key Laboratory of Transvascular Implantation Devices, Hangzhou City, Zhejiang Province, P.R. China
- China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou, China
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Zhou W, Yu C, Meng T, Jiang Q, Yu F, Yuan H. Glutaminase-responsive nano-carrier for precise rejuvenation of senescent cells by restoring autophagy in chronic kidney disease treatment. Int J Pharm 2025; 674:125469. [PMID: 40089039 DOI: 10.1016/j.ijpharm.2025.125469] [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: 11/23/2024] [Revised: 02/21/2025] [Accepted: 03/11/2025] [Indexed: 03/17/2025]
Abstract
Cellular senescence disrupts tissue homeostasis and diminishes physiological integrity, leading to the accumulation of senescent cells (SCs) in multiple senescence-associated diseases such as chronic kidney disease (CKD). Treatment of SCs has been approved to be a feasible approach to these diseases. However, curing SCs in different cell types remains challenging. In this study, we leveraged the high expression of glutaminase (GLS) in SCs to develop a drug delivery system utilizing γ-poly glutamic acid (γ-PGA) conjugated with octadecylamine (ODA) to encapsulate rapamycin (RP), resulting in a GLS-responsive drug delivery system, designated as RPPO. In a model of drug induced senescence, the γ-PGA component of RPPO was degraded by cellular GLS, facilitating the release of encapsulated RP and rejuvenating SCs by restoring the autophagic capacity. Additionally, in a model of CKD in mice, RPPO enhanced recovery by rejuvenating SCs, reducing fibrosis, and alleviating inflammation. Thus, this senescent cell-responsive drug delivery system presents a novel approach for the treatment of CKD.
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Affiliation(s)
- Wentao Zhou
- College of Pharmaceutical Science, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058 China
| | - Caini Yu
- College of Pharmaceutical Science, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058 China
| | - Tingting Meng
- College of Pharmaceutical Science, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058 China
| | - Qi Jiang
- College of Pharmaceutical Science, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058 China
| | - Fangying Yu
- Department of Diagnostic Ultrasound and Echocardiography, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016 China.
| | - Hong Yuan
- College of Pharmaceutical Science, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058 China.
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18
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Zhang ZJ, Casiraghi F, Perkins GB, Baldwin WM, Fairchild RL. Can mouse kidney transplant models inform mechanisms of injury and acceptance in clinical kidney transplantation? Am J Transplant 2025:S1600-6135(25)00172-8. [PMID: 40209906 DOI: 10.1016/j.ajt.2025.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Revised: 03/12/2025] [Accepted: 04/02/2025] [Indexed: 04/12/2025]
Abstract
Despite standard-of-care immunosuppression, acute rejection remains commonly observed in kidney transplants and leads to chronic graft injury and failure in many transplanted patients. Mechanisms underlying acute and chronic kidney graft injury are incompletely understood, undermining the development and implementation of therapeutic strategies to improve outcomes. This compels the use of preclinical kidney transplant models to identify components and mechanisms mediating acute and chronic graft injury. Mouse models have been instrumental in establishing basic principles of alloimmune responses and the rejection of heart allografts. There is increasing use of mouse models to extend these studies to kidney transplantation, but the relevance of the findings to clinical kidney transplants remains under scrutiny. Here, we discuss the strengths and weaknesses of mouse models of kidney allograft responses and injury. Although obvious weaknesses arise when considering the relevance to clinical kidney transplants, there are new models that recapitulate many features of kidney graft injury in the clinical scenario and have much to contribute to understanding innate and donor alloantigen-specific mechanisms underlying kidney allograft injury. As in most preclinical studies, the pertinent use of kidney allogeneic transplants in mice comes down to the judicious choice of test questions and the choice of appropriate donors and recipients for the chosen model.
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Affiliation(s)
- Zheng Jenny Zhang
- Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA; Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Federica Casiraghi
- Istituto di Ricerche Farmacologiche Mario Negri Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Bergamo, Italy
| | - Griffith Boord Perkins
- Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia
| | - William M Baldwin
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland, Ohio, USA; Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, USA
| | - Robert L Fairchild
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland, Ohio, USA; Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, USA.
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19
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Huang Y, Zhao L, Zhao Y, Fan Y, Gao L, Lu H, Wang X, Mo D, Wang D. Anti-Radiofibrosis Effect of Dicliptera chinensis Polysaccharide on Rat Dermal Fibroblasts Via The TGF-β1/Smads/CTGF Signaling Pathway. Int Dent J 2025; 75:1338-1347. [PMID: 39394033 PMCID: PMC11976618 DOI: 10.1016/j.identj.2024.09.024] [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: 07/25/2024] [Revised: 09/08/2024] [Accepted: 09/19/2024] [Indexed: 10/13/2024] Open
Abstract
OBJECTIVE Radiotherapy is an effective treatment for head and neck cancer; however, irradiated normal tissues are inevitably damaged, resulting in skin radioactive fibrosis. Dicliptera chinensis polysaccharide (DCP), the primary active compound extracted from the natural medicinal Dicliptera chinensis, exhibits antioxidant, anti-inflammatory, and anti-radiation properties. In this study, we investigated the protective effects of DCP against radioactive fibrosis in rat dermal fibroblasts (RDF) and explored the underlying mechanisms involved. DESIGN RDFs were treated with DCP, and the CCK8 assay was used to determine cellular activity. The rates of apoptosis and cell cycle progression were detected using flow cytometry. mRNA expression levels were quantified using real-time polymerase chain reaction. Protein levels were analysed through Western blotting and immunofluorescence staining RESULTS: DCP reduced radiation-induced apoptosis, and the cell cycle G2/M arrest was alleviated. Furthermore, DCP decreased the expression of key fibrosis-related markers, including α-SMA, TGF-β1, Smad3, and CTGF. CONCLUSION DCP exhibits a protective effect against radiation-induced fibrosis.
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Affiliation(s)
- Yude Huang
- College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi, China; Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Nanning, China; Guangxi Clinical Medical Research Center for craniofacial Deformity, Nanning, China
| | - Lixiang Zhao
- College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi, China; Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Nanning, China; Guangxi Clinical Medical Research Center for craniofacial Deformity, Nanning, China
| | - Yanfei Zhao
- College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi, China; Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Nanning, China; Guangxi Clinical Medical Research Center for craniofacial Deformity, Nanning, China
| | - Yiyang Fan
- College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi, China; Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Nanning, China; Guangxi Clinical Medical Research Center for craniofacial Deformity, Nanning, China
| | - Linjing Gao
- College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi, China; Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Nanning, China; Guangxi Clinical Medical Research Center for craniofacial Deformity, Nanning, China
| | - Haoyu Lu
- College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi, China; Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Nanning, China; Guangxi Clinical Medical Research Center for craniofacial Deformity, Nanning, China
| | - Xian Wang
- College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi, China; Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Nanning, China; Guangxi Clinical Medical Research Center for craniofacial Deformity, Nanning, China
| | - Dongqin Mo
- College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi, China; Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Nanning, China; Guangxi Clinical Medical Research Center for craniofacial Deformity, Nanning, China
| | - Daiyou Wang
- College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi, China.
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20
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Peng Y, Mei S, Qi X, Tang R, Yang W, Feng J, Zhou Y, Huang X, Qian G, Xing S, Gao Y, Xu Q, He Z. PGC-1α mediates migrasome secretion accelerating macrophage-myofibroblast transition and contributing to sepsis-associated pulmonary fibrosis. Exp Mol Med 2025; 57:759-774. [PMID: 40164683 PMCID: PMC12046055 DOI: 10.1038/s12276-025-01426-z] [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: 09/23/2024] [Revised: 12/29/2024] [Accepted: 01/01/2025] [Indexed: 04/02/2025] Open
Abstract
Sepsis-associated pulmonary fibrosis (SAPF) is a critical pathological stage in the progression of sepsis-induced acute respiratory distress syndrome. While the aggregation and activation of lung fibroblasts are central to the initiation of pulmonary fibrosis, the macrophage-myofibroblast transition (MMT) has recently been identified as a novel source of fibroblasts in this context. However, the mechanisms driving MMT remain inadequately understood. Given the emerging role of migrasomes (novel extracellular vesicles mediating intercellular communication), we investigated their involvement in pulmonary fibrosis. Here we utilized a lipopolysaccharide-induced SAPF mouse model and an in vitro co-culture system of fibroblasts and macrophages to observe the MMT process during SAPF. We found that lipopolysaccharide exposure suppresses PGC-1α expression in lung fibroblasts, resulting in mitochondrial dysfunction and the accumulation of cytosolic mitochondrial DNA (mtDNA). This dysfunction promotes the secretion of mtDNA-containing migrasomes, which, in turn, initiate the MMT process and contribute to fibrosis progression. Notably, the activation of PGC-1α mitigates mitochondrial dysfunction, reduces mtDNA-migrasome release, inhibits MMT and alleviates SAPF. In conclusion, our study identifies the suppression of PGC-1α in lung fibroblasts and the subsequent release of mtDNA migrasomes as a novel mechanism driving MMT in SAPF. These findings suggest that targeting the crosstalk between fibroblasts and immune cells mediated by migrasomes could represent a promising therapeutic strategy for SAPF.
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Affiliation(s)
- Yawen Peng
- Department of Critical Care Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, Shanghai, China
| | - Shuya Mei
- Department of Critical Care Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, Shanghai, China
| | - Xiaohui Qi
- Department of Cardiovascular Surgery, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ri Tang
- Department of Critical Care Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, Shanghai, China
| | - Wenyu Yang
- Department of Critical Care Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, Shanghai, China
| | - Jinhua Feng
- Department of Critical Care Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, Shanghai, China
| | - Yang Zhou
- Department of Critical Care Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, Shanghai, China
| | - Xi Huang
- Department of Critical Care Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, Shanghai, China
| | - Guojun Qian
- Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, Shanghai, China
| | - Shunpeng Xing
- Department of Critical Care Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuan Gao
- Department of Critical Care Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Qiaoyi Xu
- Department of Critical Care Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, Shanghai, China.
| | - Zhengyu He
- Department of Critical Care Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, Shanghai, China.
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21
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Mu YF, Mao ZH, Pan SK, Liu DW, Liu ZS, Wu P, Gao ZX. Macrophage-driven inflammation in acute kidney injury: Therapeutic opportunities and challenges. Transl Res 2025; 278:1-9. [PMID: 39954848 DOI: 10.1016/j.trsl.2025.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Revised: 02/08/2025] [Accepted: 02/12/2025] [Indexed: 02/17/2025]
Abstract
Acute kidney injury (AKI) is increasingly being recognized as a systemic disorder associated with significant morbidity and mortality. AKI manifests with extensive cellular damage, necrosis, and an intense inflammatory response, often leading to late-stage interstitial fibrosis. Although the mechanisms underlying renal injury and repair remain poorly understood, macrophages (pivotal inflammatory cells) play central roles in AKI. They undergo polarization into pro-inflammatory and anti-inflammatory phenotypes, contributing dynamically to both the injury and repair processes while maintaining homeostasis. Macrophages modulate microenvironmental inflammation by releasing extracellular vesicles (EVs) containing pro- or anti-inflammatory signaling molecules, thereby influencing the regulation of tissue injury. The injured tissue cells release EVs and activate local macrophages to initiate these responses. Our bibliometric analysis indicated that a shift has occurred in AKI macrophage research towards therapeutic strategies and clinical translation, focusing on macrophage-targeted therapies, including exosomes and nanoparticles. This review highlights the roles and mechanisms of macrophage activation, phenotypic polarization, and trans-differentiation in AKI and discusses macrophage-based approaches for AKI prevention and treatment. Understanding the involvement of macrophages in AKI contributes to the comprehension of related immune mechanisms and lays the groundwork for novel diagnostic and therapeutic avenues.
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Affiliation(s)
- Ya-Fan Mu
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Institute of Nephrology, Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou, China; Henan Province Research Center for Kidney Disease, Zhengzhou, China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
| | - Zi-Hui Mao
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Institute of Nephrology, Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou, China; Henan Province Research Center for Kidney Disease, Zhengzhou, China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
| | - Shao-Kang Pan
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Institute of Nephrology, Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou, China; Henan Province Research Center for Kidney Disease, Zhengzhou, China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
| | - Dong-Wei Liu
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Institute of Nephrology, Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou, China; Henan Province Research Center for Kidney Disease, Zhengzhou, China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
| | - Zhang-Suo Liu
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Institute of Nephrology, Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou, China; Henan Province Research Center for Kidney Disease, Zhengzhou, China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
| | - Peng Wu
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Institute of Nephrology, Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou, China; Henan Province Research Center for Kidney Disease, Zhengzhou, China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China.
| | - Zhong-Xiuzi Gao
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Institute of Nephrology, Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou, China; Henan Province Research Center for Kidney Disease, Zhengzhou, China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China.
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22
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Wang W, Jin Y, Liu MK, Zhang SY, Chen H, Song J. Current Progress of Hederagenin and Its Derivatives for Disease Therapy (2017-Present). Molecules 2025; 30:1275. [PMID: 40142049 PMCID: PMC11944430 DOI: 10.3390/molecules30061275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 02/24/2025] [Accepted: 03/03/2025] [Indexed: 03/28/2025] Open
Abstract
Natural products have emerged as crucial sources of biologically active compounds, holding promise for applications in drug development. Among the extensively researched pentacyclic triterpenes, hederagenin (HG) stands out for its diverse biological activities and serves as a valuable scaffold for synthesizing novel derivatives. These derivatives hold significant promise for the development of novel therapeutic agents aimed at treating a wide range of diseases. Over the past years, a multitude of HG derivatives with varied bioactivities have been synthesized through chemical modifications. This review article consolidates the most recent findings (since 2017) on HG derivatives, emphasizing their biological effects and mechanisms of action in both in vitro and in vivo models. The objective of this compilation is to offer insights and direct future research endeavors in the realm of HG.
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Affiliation(s)
- Wang Wang
- Luoyang Key Laboratory of Organic Functional Molecules, School of Food and Drug, Luoyang Normal University, Luoyang 471934, China; (W.W.); (Y.J.); (M.-K.L.)
| | - Yan Jin
- Luoyang Key Laboratory of Organic Functional Molecules, School of Food and Drug, Luoyang Normal University, Luoyang 471934, China; (W.W.); (Y.J.); (M.-K.L.)
| | - Meng-Ke Liu
- Luoyang Key Laboratory of Organic Functional Molecules, School of Food and Drug, Luoyang Normal University, Luoyang 471934, China; (W.W.); (Y.J.); (M.-K.L.)
| | - Sai-Yang Zhang
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China;
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou 450001, China
| | - Hong Chen
- Luoyang Key Laboratory of Organic Functional Molecules, School of Food and Drug, Luoyang Normal University, Luoyang 471934, China; (W.W.); (Y.J.); (M.-K.L.)
| | - Jian Song
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China;
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou 450001, China
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23
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Yao Q, Zheng X, Zhang X, Wang Y, Zhou Q, Lv J, Zheng L, Lan J, Chen W, Chen J, Chen D. METTL3 Potentiates M2 Macrophage-Driven MMT to Aggravate Renal Allograft Fibrosis via the TGF-β1/Smad3 Pathway. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2412123. [PMID: 39869489 PMCID: PMC11923867 DOI: 10.1002/advs.202412123] [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: 09/29/2024] [Revised: 01/09/2025] [Indexed: 01/29/2025]
Abstract
METTL3, a key enzyme in N6-methyladenosine (m6A) modification, plays a crucial role in the progression of renal fibrosis, particularly in chronic active renal allograft rejection (CAR). This study explored the mechanisms by which METTL3 promotes renal allograft fibrosis, focusing on its role in the macrophage-to-myofibroblast transition (MMT). Using a comprehensive experimental approach, including TGF-β1-induced MMT cell models, METTL3 conditional knockout (METTL3 KO) mice, and renal biopsy samples from patients with CAR, the study investigates the involvement of METTL3/Smad3 axis in driving MMT and renal fibrosis during the episodes of CAR. We found that elevated m6A modification and METTL3 levels strongly correlated with enhanced MMT and increased fibrotic severity. METTL3 knockout (METTL3 KO) significantly increased the m6A modification of Smad3, decreased Smad3 expression, and inhibited M2-driven MMT. Smad3 knockdown with siRNA (siSmad3) further inhibited M2-driven MMT, while Smad3 overexpression rescued the inhibitory effects of METTL3 silencing, restoring M2-driven MMT and fibrotic tissue damage. Additionally, the METTL3 inhibitor STM2457 effectively reversed M2-driven MMT and alleviated fibrotic tissue damage in CAR. These findings highlight that METTL3 enhances M2-driven MMT in renal fibrosis during CAR by promoting the TGF-β1/Smad3 axis, suggesting that METTL3 is a promising therapeutic target for mitigating renal fibrosis in CAR.
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Affiliation(s)
- Qinfan Yao
- Kidney Disease CenterThe First Affiliated HospitalZhejiang University School of MedicineHangzhou310003China
- Key Laboratory of Kidney Disease Prevention and Control TechnologyHangzhouZhejiang310003China
- National Key Clinical Department of Kidney DiseasesHangzhou310003China
- Institute of NephropathyZhejiang UniversityHangzhou310003China
- Zhejiang Clinical Research Center of Kidney and Urinary System DiseaseHangzhou310003China
| | - Xiaoxiao Zheng
- Cancer Institute of lntegrated Traditional Chinese and Western MedicineKey Laboratory of Cancer Prevention and Therapy Combining Traditional Chinese and Western Medicine, Zhejiang Key Laboratory of Disease‐Syndrome Integrated Cancer Prevention and TreatmentZhejiang Academy of Traditional Chinese MedicineHangzhouZhejiang310012China
| | - Xinyi Zhang
- Kidney Disease CenterThe First Affiliated HospitalZhejiang University School of MedicineHangzhou310003China
- Key Laboratory of Kidney Disease Prevention and Control TechnologyHangzhouZhejiang310003China
- National Key Clinical Department of Kidney DiseasesHangzhou310003China
- Institute of NephropathyZhejiang UniversityHangzhou310003China
- Zhejiang Clinical Research Center of Kidney and Urinary System DiseaseHangzhou310003China
| | - Yucheng Wang
- Kidney Disease CenterThe First Affiliated HospitalZhejiang University School of MedicineHangzhou310003China
- Key Laboratory of Kidney Disease Prevention and Control TechnologyHangzhouZhejiang310003China
- National Key Clinical Department of Kidney DiseasesHangzhou310003China
- Institute of NephropathyZhejiang UniversityHangzhou310003China
- Zhejiang Clinical Research Center of Kidney and Urinary System DiseaseHangzhou310003China
| | - Qin Zhou
- Kidney Disease CenterThe First Affiliated HospitalZhejiang University School of MedicineHangzhou310003China
- Key Laboratory of Kidney Disease Prevention and Control TechnologyHangzhouZhejiang310003China
- National Key Clinical Department of Kidney DiseasesHangzhou310003China
- Institute of NephropathyZhejiang UniversityHangzhou310003China
- Zhejiang Clinical Research Center of Kidney and Urinary System DiseaseHangzhou310003China
| | - Junhao Lv
- Kidney Disease CenterThe First Affiliated HospitalZhejiang University School of MedicineHangzhou310003China
- Key Laboratory of Kidney Disease Prevention and Control TechnologyHangzhouZhejiang310003China
- National Key Clinical Department of Kidney DiseasesHangzhou310003China
- Institute of NephropathyZhejiang UniversityHangzhou310003China
- Zhejiang Clinical Research Center of Kidney and Urinary System DiseaseHangzhou310003China
| | - Li Zheng
- Cancer Institute of lntegrated Traditional Chinese and Western MedicineKey Laboratory of Cancer Prevention and Therapy Combining Traditional Chinese and Western Medicine, Zhejiang Key Laboratory of Disease‐Syndrome Integrated Cancer Prevention and TreatmentZhejiang Academy of Traditional Chinese MedicineHangzhouZhejiang310012China
| | - Jiahua Lan
- Cancer Institute of lntegrated Traditional Chinese and Western MedicineKey Laboratory of Cancer Prevention and Therapy Combining Traditional Chinese and Western Medicine, Zhejiang Key Laboratory of Disease‐Syndrome Integrated Cancer Prevention and TreatmentZhejiang Academy of Traditional Chinese MedicineHangzhouZhejiang310012China
| | - Wei Chen
- Department of General SurgerySir Run‐Run Shaw HospitalZhejiang University School of MedicineHangzhouZhejiang310016China
- Provincial Key Laboratory of Precise Diagnosis and Treatment of Abdominal InfectionSir Run‐Run Shaw HospitalZhejiang University School of MedicineHangzhouZhejiang310016China
| | - Jianghua Chen
- Kidney Disease CenterThe First Affiliated HospitalZhejiang University School of MedicineHangzhou310003China
- Key Laboratory of Kidney Disease Prevention and Control TechnologyHangzhouZhejiang310003China
- National Key Clinical Department of Kidney DiseasesHangzhou310003China
- Institute of NephropathyZhejiang UniversityHangzhou310003China
- Zhejiang Clinical Research Center of Kidney and Urinary System DiseaseHangzhou310003China
| | - Dajin Chen
- Kidney Disease CenterThe First Affiliated HospitalZhejiang University School of MedicineHangzhou310003China
- Key Laboratory of Kidney Disease Prevention and Control TechnologyHangzhouZhejiang310003China
- National Key Clinical Department of Kidney DiseasesHangzhou310003China
- Institute of NephropathyZhejiang UniversityHangzhou310003China
- Zhejiang Clinical Research Center of Kidney and Urinary System DiseaseHangzhou310003China
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24
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Sun S, Han B, Ren G, Fan L, Sun J, Li H, Huang J. MTHFD2 stabilizes LOX expression through RNA methylation modification to promote sepsis-induced acute kidney injury progression. Hum Cell 2025; 38:62. [PMID: 40009304 DOI: 10.1007/s13577-025-01189-9] [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: 09/14/2024] [Accepted: 02/14/2025] [Indexed: 02/27/2025]
Abstract
Myofibroblasts combine features of fibroblasts and smooth muscle cells, and they are reactive cells present under injury conditions. This study was performed to explore the mechanism that methylenetetrahydrofolate dehydrogenase/cyclohydrolase 2 (MTHFD2) mediated m6A modification in sepsis-induced AKI (SAKI) through regulating the collagen accumulation in myofibroblasts. Gene expression microarrays related to SAKI were obtained from the GEO database, and the hub protein involved was screened using PPI. The SAKI mice were induced by cecal ligation and puncture (CLP). MTHFD2 expression was significantly elevated in the kidneys of CLP-induced mice, and SAKI was ameliorated by knocking down MTHFD2 in kidney tissues. MTHFD2 promoted N6-methyladenosine (m6A) modification in kidney tissues of CLP-induced mice by increasing the content of methylated donor s-adenosylmethionine (SAM). MTHFD2 enhanced LOX mRNA stability in an m6A modification-dependent manner, thereby promoting its expression. Knockdown of MTHFD2 inhibited collagen accumulation in myofibroblasts, whereas overexpression of LOX accelerated fibrosis and SAKI in mice in the presence of sh-MTHFD2. In conclusion, our results show that MTHFD2 promotes LOX expression in an m6A-dependent manner, thereby mediating SAKI progression.
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Affiliation(s)
- Shudong Sun
- The School of Clinical Medicine, Fujian Medical University, No.1 Xuefu North Road, Fuzhou, 350122, Fujian, People's Republic of China
- Department of Burns and Wound Repair, Weifang People's Hospital, Shandong Second Medical University, Weifang, 261000, Shandong, People's Republic of China
| | - Baoyi Han
- Department of Anesthesiology, Guangdong Woman and Child Health Hospital, Guangzhou, 511450, Guangdong, People's Republic of China
| | - Guohui Ren
- Medical Department of Weifang People's Hospital, Shandong Second Medical University, Weifang, 261000, Shandong, People's Republic of China
| | - Lei Fan
- Department of Burns and Wound Repair, Weifang People's Hospital, Shandong Second Medical University, Weifang, 261000, Shandong, People's Republic of China
| | - Junchao Sun
- The School of Clinical Medicine, Shandong Second Medical University, Weifang, 261053, Shandong, People's Republic of China
| | - Huiling Li
- Department of Burns and Wound Repair, Weifang People's Hospital, Shandong Second Medical University, Weifang, 261000, Shandong, People's Republic of China
| | - Jiyi Huang
- The School of Clinical Medicine, Fujian Medical University, No.1 Xuefu North Road, Fuzhou, 350122, Fujian, People's Republic of China.
- Department of Nephrology, Xiamen Key Laboratory of Precision Diagnosis and Treatment of Chronic Kidney Disease, The Fifth Hospital of Xiamen, Xiamen, 361101, Fujian, People's Republic of China.
- Department of Nephrology, Fujian Clinical Research Center for Chronic Glomerular Disease, The First Affiliated Hospital of Xiamen University, Xiamen, 361102, Fujian, People's Republic of China.
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Xia Y, Ye Z, Li B, Yan X, Yuan T, Li L, Song B, Yu W, Rao T, Ning J, Zhu J, Li X, Mei S, Mao Z, Zhou X, Cheng F. EZH2-mediated macrophage-to-myofibroblast transition contributes to calcium oxalate crystal-induced kidney fibrosis. Commun Biol 2025; 8:286. [PMID: 39987296 PMCID: PMC11846861 DOI: 10.1038/s42003-025-07735-3] [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: 05/14/2024] [Accepted: 02/13/2025] [Indexed: 02/24/2025] Open
Abstract
Long-term nephrocalcinosis leads to kidney injury, fibrosis, and even chronic kidney disease (CKD). Macrophage-to-myofibroblast transition (MMT) has been identified as a new mechanism in CKD, however, the effect of MMT in calcium oxalate (CaOx)-induced kidney fibrosis remains unclear. In this study, abundant MMT cells are identified by immunofluorescence (IF) and flow cytometry in kidney tissues of patients with CaOx-related CKD, a male mouse model, and CaOx-treated macrophages. Clodronate liposome (CLO)-mediated macrophage depletion attenuates fibrosis in male nephrocalcinosis mice. Transcriptomic sequencing reveals that histone methyltransferase (HMTs), EZH2, is highly expressed in nephrocalcinosis. Ezh2 inducible knock-out or inhibition by GSK-126 attenuates MMT and renal fibrosis. Mechanistically, ChIP and transcriptomic sequencing show that EZH2 inhibition reduces the enrichment of H3K27me3 on the Dusp23 gene promoter and elevates Dusp23 expression. The Co-IP and molecular docking analysis shows that DUSP23 mediates the dephosphorylation of pSMAD3 (Ser423/425). Thus, our study found that EZH2 promotes kidney fibrosis by meditating MMT via the DUSP23/SMAD3 pathway in nephrocalcinosis.
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Affiliation(s)
- Yuqi Xia
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Zehua Ye
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Bojun Li
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Xinzhou Yan
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Tianhui Yuan
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Lei Li
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Baofeng Song
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Weimin Yu
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Ting Rao
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Jinzhuo Ning
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Jiefu Zhu
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Xing Li
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Shuqin Mei
- Department of Nephrology, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Zhiguo Mao
- Department of Nephrology, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Xiangjun Zhou
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
| | - Fan Cheng
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
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Fu T, Zhou J, Yang L, Wang J, Li H, Shan Y, Gao H, Xie C, Jiang D, Zhang L, Ma J, Pan Q, Xu M, Zhang M, Gu S. Neutrophil-induced pyroptosis promotes survival in patients with hepatoblastoma. Cancer Immunol Immunother 2025; 74:106. [PMID: 39932547 PMCID: PMC11813845 DOI: 10.1007/s00262-024-03922-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Accepted: 12/11/2024] [Indexed: 02/14/2025]
Abstract
BACKGROUND Hepatoblastoma (HB) is the predominant hepatic malignancy among children. Despite therapeutic options for HB were gradually refined in recent years, patients with metastasis suffer from an unsatisfactory prognosis. Pyroptosis is a type of programmed and inflammatory necrosis. Neutrophils are crucial in innate immunity, which were shown to be associated with tumor progression. Our study strived to unravel the relationship between neutrophil-induced pyroptosis (NIP) and HB. METHODS The clinical and bulk RNA sequencing data of 38 patients with HB were obtained from Shanghai Children's Medical Center. We established NIP score based on the LASSO regression. The single-cell RNA sequencing data (GSE186975) were used for for key genes identification, cellular communication, and differentiation trajectories of neutrophils. KEGG, GO, GSVA, and ssGSEA enrichment were used to analyze biological functions, including neutrophil extracellular traps (NETs), NOD-like receptors pathway, neutrophil activation, neutrophil-mediated cytotoxicity, and others. RESULTS We constructed a NIP score based on the expression of three genes related to neutrophil and pyroptosis, namely ELANE, CASP1, and NOD2, which was positively correlated with a favorable prognosis of HB. Moreover, we clarified the function of ELANE in HB microenvironmwnt. Immunohistochemistry and transcriptome analysis unraveled a significant correlation between NETs and pyroptosis in HB, suggesting the key role of NETs-related neutrophils in inducing pyroptosis and prolonging survival. We also found upregulated tumor-promoting and immunosuppression-related pathways in the HB microenvironment. In addition, we clarified the growth trajectories and phenotypic changes of neutrophils in the immune microenvironment of HB, which can serve as potential targets for immunotherapy. CONCLUSIONS The novel NIP score for patients with HB shows high predictive value for survival. Moreover, we identified biological function, cellular communication, and growth trajectories of neutrophils in HB. Our findings broaden insights into the treatment of HB.
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Affiliation(s)
- Tingyi Fu
- Department of General Surgery, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China
| | - Jiquan Zhou
- Department of General Surgery, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China
| | - Liyuan Yang
- Department of General Surgery, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China
| | - Jing Wang
- Department of General Surgery, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China
| | - Hui Li
- Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Pediatric Translational Medicine Institute, Shanghai Children's Medical Center Affiliated to Shanghai, Jiao Tong University School of Medicine, 1678 Dongfang Road, Shanghai, 200127, People's Republic of China
| | - Yuhua Shan
- Department of General Surgery, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China
| | - Hongxiang Gao
- Department of General Surgery, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China
| | - Chenjie Xie
- Department of General Surgery, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China
| | - Dapeng Jiang
- Department of General Surgery, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China
| | - Lei Zhang
- Department of General Surgery, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China
| | - Ji Ma
- Department of Laboratory Medicine, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China
| | - Qiuhui Pan
- Department of Laboratory Medicine, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China
| | - Min Xu
- Department of General Surgery, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China
| | - Min Zhang
- Pediatric Translational Medicine Institute and Pediatric Congenital Heart Disease Institute, Shanghai Children's Medical Center Affiliated to Shanghai, Jiao Tong University School of Medicine, 1678 Dongfang Road, Shanghai, 200127, People's Republic of China.
| | - Song Gu
- Department of General Surgery, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China.
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Ha S, Son M, Kim J, Kim D, Kim MJ, Yoo J, Kim BM, Kim D, Chung HY, Chung KW. Gender Differences in Adenine Diet-Induced Kidney Toxicity: The Impact of 17β-Estradiol on Renal Inflammation and Fibrosis. Int J Mol Sci 2025; 26:1358. [PMID: 39941126 PMCID: PMC11818771 DOI: 10.3390/ijms26031358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Revised: 02/03/2025] [Accepted: 02/04/2025] [Indexed: 02/16/2025] Open
Abstract
Chronic kidney disease (CKD) involves ongoing impairment of kidney function and structural changes. Previous studies indicated that males have a substantially higher prevalence of CKD than those observed in females. Here, we compared the gender differences in CKD development by comparing age-matched male and female mice subjected to a 0.25% adenine diet (AD) for two weeks. Male mice showed a significantly greater decrease in kidney function than female mice, as evidenced by the elevated blood urea nitrogen levels (M-AD: 160 ± 5 mg/dL, F-AD: 90 ± 4 mg/dL; p < 0.001). Furthermore, male mice kidneys exhibited pronounced tubule dilation and kidney damage, as detected by histological and biochemical methods. The extent of fibrosis was quantified using multiple biological methods, revealing a greater degree of fibrosis in male kidneys. We next indicated the inflammatory responses in the kidneys. Similar to the extent of fibrosis, AD-fed male mice showed significantly increased levels of pro-inflammatory markers, including cytokine expression and infiltration of immune cell, compared to female mice. Based on in vivo observations, the anti-inflammatory and anti-fibrotic effects of 17β-estradiol (E2) were further evaluated in vitro conditions. E2 pre-treatment significantly reduced lipopolysaccharide-induced inflammatory response through inhibition of the nuclear factor-kappa B (NF-κB) pathway in NRK52E renal epithelial cells. In NRK49F renal fibroblasts, E2 pre-treatment also reduced TGFβ-induced fibrotic responses. We further demonstrated that E2 markedly decreased fibrosis and inflammation in AD-fed mouse kidneys. Our observations revealed that male mice kidneys exhibited a heightened inflammatory and fibrotic response compared to female mice kidneys. Additionally, our findings suggest that the observed sex differences may be partially attributed to the potential anti-inflammatory and anti-fibrotic effects of E2.
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Affiliation(s)
- Sugyeong Ha
- Department of Pharmacy and Research Institute for Drug Development, College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea; (S.H.); (M.S.); (J.K.); (D.K.); (M.-J.K.); (J.Y.); (B.M.K.); (H.Y.C.)
| | - Minjung Son
- Department of Pharmacy and Research Institute for Drug Development, College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea; (S.H.); (M.S.); (J.K.); (D.K.); (M.-J.K.); (J.Y.); (B.M.K.); (H.Y.C.)
| | - Jeongwon Kim
- Department of Pharmacy and Research Institute for Drug Development, College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea; (S.H.); (M.S.); (J.K.); (D.K.); (M.-J.K.); (J.Y.); (B.M.K.); (H.Y.C.)
| | - Doyeon Kim
- Department of Pharmacy and Research Institute for Drug Development, College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea; (S.H.); (M.S.); (J.K.); (D.K.); (M.-J.K.); (J.Y.); (B.M.K.); (H.Y.C.)
| | - Mi-Jeong Kim
- Department of Pharmacy and Research Institute for Drug Development, College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea; (S.H.); (M.S.); (J.K.); (D.K.); (M.-J.K.); (J.Y.); (B.M.K.); (H.Y.C.)
| | - Jian Yoo
- Department of Pharmacy and Research Institute for Drug Development, College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea; (S.H.); (M.S.); (J.K.); (D.K.); (M.-J.K.); (J.Y.); (B.M.K.); (H.Y.C.)
| | - Byeong Moo Kim
- Department of Pharmacy and Research Institute for Drug Development, College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea; (S.H.); (M.S.); (J.K.); (D.K.); (M.-J.K.); (J.Y.); (B.M.K.); (H.Y.C.)
| | - Donghwan Kim
- Functional Food Materials Research Group, Korea Food Research Institute, Wanju-gun 55365, Republic of Korea;
| | - Hae Young Chung
- Department of Pharmacy and Research Institute for Drug Development, College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea; (S.H.); (M.S.); (J.K.); (D.K.); (M.-J.K.); (J.Y.); (B.M.K.); (H.Y.C.)
| | - Ki Wung Chung
- Department of Pharmacy and Research Institute for Drug Development, College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea; (S.H.); (M.S.); (J.K.); (D.K.); (M.-J.K.); (J.Y.); (B.M.K.); (H.Y.C.)
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Yang Z, Shi L, Wang Y, Zhou D, Zhang C, Lin Y. Unveiling the Potential of Tetrahedral DNA Frameworks in Clinical Medicine: Mechanisms, Advances, and Future Perspectives. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2025; 21:e2410162. [PMID: 39707665 DOI: 10.1002/smll.202410162] [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: 10/29/2024] [Revised: 11/24/2024] [Indexed: 12/23/2024]
Abstract
As deoxyribonucleic acis (DNA) nanotechnology advances, DNA, a fundamental biological macromolecule, has been employed to treat various clinical diseases. Among the advancements in this field, tetrahedral frameworks nucleic acids (tFNAs) have gained significant attention due to their straightforward design, structural simplicity, low cost, and high yield since their introduction by Turberfield in the early 2000s. Due to its stable spatial structure, tFNAs can resist the impact of innate immune responses on DNA and nuclease activity. Meanwhile, structural programmability of tFNAs allows for the development of static tFNA-based nanomaterials through the engineering of functional oligonucleotides or therapeutic molecules and dynamic tFNAs through the attachment of stimuli-responsive DNA apparatuses. This review first summarizes the key merits of tFNAs, including natural biocompatibility, biodegradability, structural stability, unparalleled programmability, functional diversity, and efficient cellular internalization. Based on these strengths, this review comprehensively analyzes applications of tFNAs in different clinical settings, including orthopedics, stomatology, urinary system diseases, liver-related diseases, tumors, infection, neural system diseases, ophthalmic diseases, and immunoprophylaxis. We also discuss the limitations of tFNAs and the challenges encountered in preclinical studies. This review provides new perspectives for future research and valuable guidance for researchers working in this field.
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Affiliation(s)
- Zhengyang Yang
- Department of General Surgery, State Key Lab of Digestive Health, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
| | - Lin Shi
- Department of Orthopedics, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
| | - Yun Wang
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Centre for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Dongfang Zhou
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Chao Zhang
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
| | - Yunfeng Lin
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Centre for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
- Sichuan Provincial Engineering Research Center of Oral Biomaterials, Chengdu, 610041, China
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Li P, Ji W, Zhang B, Jia H, Wang J, Sun Z, Wang Y, Wang W, Qi F. FPR1 affects acute rejection in kidney transplantation by regulating iron metabolism in neutrophils. Mol Med 2025; 31:23. [PMID: 39849390 PMCID: PMC11758745 DOI: 10.1186/s10020-025-01077-w] [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: 02/29/2024] [Accepted: 01/10/2025] [Indexed: 01/25/2025] Open
Abstract
BACKGROUND Acute rejection (AR) is one of the significant factors contributing to poor prognosis in patients following kidney transplantation. Neutrophils are the main cause of early host-induced tissue injury. This paper intends to investigate the possible mechanisms of neutrophil involvement in acute rejection in renal transplantation. METHODS Samples were analyzed for their relationship with immune cells using CIBERSORT. WGCNA was used to identify modules with high relevance to neutrophils and hub genes in the modules were extracted. The effect on neutrophil function after blocking formyl peptide receptor 1 (FPR1) was tested in vitro experiments. The effects of blocking FPR1 on neutrophil function as well as acute rejection were tested in vivo after constructing a mouse kidney transplant model. RESULTS The proportion of neutrophils was higher in the AR group than in the non-rejection group, and FPR1 was identified as an important gene in the regulation of acute rejection in kidney transplantation by neutrophils. At the cellular level, blocking FPR1 inhibited the activation of the ERK1/2 pathway, decreased ferrous ion content, affected the expression of iron metabolism-related proteins, and suppressed the formation of NETs. In the acute rejection model of renal transplantation, blockade of FPR1 decreased graft neutrophil infiltration and NETs content. Meanwhile, blocking FPR1 attenuated graft injury during acute rejection. CONCLUSION This study found that FPR1 might be an important molecule involved in neutrophils during acute rejection of kidney transplantation, explored the relationship between kidney transplantation and neutrophils, and provided potential treatment methods for clinical practice.
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Affiliation(s)
- Peiyuan Li
- Department of General Surgery, Tianjin Medical University General Hospital, No. 154, Anshan Road, Heping District, Tianjin, 300052, China
| | - Wenbin Ji
- Department of General Surgery, Tianjin Medical University General Hospital, No. 154, Anshan Road, Heping District, Tianjin, 300052, China
| | - Baotong Zhang
- Department of General Surgery, Tianjin Medical University General Hospital, No. 154, Anshan Road, Heping District, Tianjin, 300052, China
| | - Haowen Jia
- Department of General Surgery, Tianjin Medical University General Hospital Airport Hospital, No.85, East Sixth Road, Dongli District, Tianjin, 300300, China
| | - Jinmiao Wang
- Department of Breast and Thyroid Surgery, Tianjin Union Medical Center, Nankai University, Tianjin, 300121, China
| | - Zhaonan Sun
- Department of General Surgery, Tianjin Medical University General Hospital, No. 154, Anshan Road, Heping District, Tianjin, 300052, China
| | - Yifan Wang
- Department of General Surgery, Tianjin Medical University General Hospital, No. 154, Anshan Road, Heping District, Tianjin, 300052, China
| | - Weiwei Wang
- Department of General Surgery, Tianjin Baodi Hospital, Tianjin Medical University Baodi Hospital, #8 Guangchuan Road, Baodi, 301800, Tianjin, China.
| | - Feng Qi
- Department of General Surgery, Tianjin Medical University General Hospital, No. 154, Anshan Road, Heping District, Tianjin, 300052, China.
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Zhong Q, Zeng J, Li Y, Zhang H, Lin T, Song T. Senescent renal tubular cells derived extracellular vesicles transported miR-20a and miR-21 induced macrophage-to-myofibroblast transition in renal fibrosis after ischemia reperfusion injury. Int J Biol Sci 2025; 21:940-954. [PMID: 39897045 PMCID: PMC11781180 DOI: 10.7150/ijbs.97579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2024] [Accepted: 12/09/2024] [Indexed: 02/04/2025] Open
Abstract
In our investigation, we aimed to shed light on the role of senescent cells in renal fibrosis, considering the observed correlation between renal tubular epithelial cell senescence and the presence of renal fibrosis. Our findings confirm the manifestation of senescence characteristics in renal tubular epithelial cells during renal fibrosis and establish their capacity to trigger a transition from macrophages to myofibroblasts, known as macrophage-myofibroblast transition (MMT). Additionally, our study uncovered that extracellular vesicles released by senescent HK-2 cells (sHK-2) play a pivotal role in facilitating MMT. Subsequently, we investigated the miRNA profile in sHK-2-derived extracellular vesicles (sHK-2-EVs) and confirmed the elevated abundance of specific miRNAs, including miR-20a-5p and miR-21-5p, compared to normal HK-2-EVs. Notably, these miRNAs possess the capability to induce M2-like polarization in macrophages and enhance the expression of TGF-β. Moreover, TGF-β can stimulate macrophages to produce miR-20a-5p and miR-21-5p, establishing a positive feedback loop that amplifies the TGF-β/Smad pathway and facilitates the process of macrophage-myofibroblast transition.
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Affiliation(s)
- Qiang Zhong
- Department of Organ Transplantation Center, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Jun Zeng
- Department of Urology, Institute of Urology, Organ Transplantation Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yue Li
- Department of Urology, Institute of Urology, Organ Transplantation Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Haohan Zhang
- Department of Urology, Institute of Urology, Organ Transplantation Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Tao Lin
- Department of Urology, Institute of Urology, Organ Transplantation Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Turun Song
- Department of Urology, Institute of Urology, Organ Transplantation Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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Lv Y, Hua Z, Lu X. Protective effects and possible mechanisms of mesenchymal stem cells and mesenchymal stem cell-derived extracellular vesicles against kidney fibrosis in animal models: a systematic review and meta-analysis. Front Pharmacol 2025; 15:1511525. [PMID: 39830341 PMCID: PMC11739157 DOI: 10.3389/fphar.2024.1511525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 12/05/2024] [Indexed: 01/22/2025] Open
Abstract
Introduction The risk of kidney fibrosis is significantly elevated in individuals with diabetes, chronic nephritis, trauma, and other underlying conditions. Concurrently, human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) and their extracellular vesicles (MSC-Exos) have gained prominence in regenerative medicine. In light of these observations, we are undertaking a meta-analysis to elucidate the influence of hUCB-MSCs and MSC-Exos on kidney fibrosis. Methods To identify eligible trials, we conducted a comprehensive search of the CNKI, PubMed, Web of Science and Wanfang databases from inception to 24 October 2022. Furthermore, the methodological quality of the included studies was evaluated using the Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) risk-of-bias tool. Besides, the weighted standard mean difference (SMD) with a 95% confidence interval (CI) was calculated using the Review Manager 5.4 software. The Stata (12.0) software was employed to assess the impact of factors on outcome heterogeneity and publication bias in the study. A total of 645 related research studies were retrieved, of which 14 that involved 219 experimental animals were included in the study. Results In comparison to the control treatment, treatment with Human UCB MSC and MSC-Exos was observed to significantly enhance renal function in animal models of kidney fibrosis. This was evidenced by a reduction in serum creatinine (Scr) levels (p < 0.00001) and blood urea nitrogen (BUN) levels (p < 0.00001), as well as reduction of CD68+ macrophages (p < 0.00001), TdT-mediated dUTP Nick-End labeling (TUNEL)+ tubular cells(p < 0.00001), α-SMA levels (p = 0.0009) and TGF-β1 (p < 0.00001). P < 0.05 is deemed to indicate a statistically significant difference. Alpha-smooth muscle actin (α-SMA) is a specific protein that is normally expressed in myofibroblasts. The term "CD68+ macrophages" refers to macrophages that express the CD68 protein on their cell surface. Both macrophages and myofibroblasts have been linked to the development of kidney fibrosis. In this study, the quantity of CD68+ macrophages and α-SMA was employed as a means of gauging the extent of renal fibrosis. Additionally, transforming growth factor beta 1 (TGF-β1) is a significant cytokine implicated in the pathogenesis of kidney fibrosis. TUNEL-positive tubular cells represent tubular cells undergoing apoptosis. It is hypothesized that this may result in a reduction of tubular apoptosis and a delay in kidney fibrosis, due to the inhibition of the transformation of macrophages into myofibroblasts (MMT) and the disruption of the kidney fibrogenic niche. Conclusion The principal findings of this preclinical systematic review indicate that hUCB MSC and MSC-Exos have a substantial protective impact against kidney fibrosis. Kidney transfer remains the final option for traditional renal fibrosis treatment. The lack of donors and high cost make it challenging for many patients to access appropriate treatment. Although this study still suffers from three shortcomings: sample size, methodological consistency and translational challenges, the hUCB MSC and MSC-Exos have been demonstrated to reduce tubular apoptosis and inhibit fibrotic progression. The hUCB MSC and MSC-Exos offer a promising alternative due to their lower price and accessibility. Nevertheless, further high-quality studies are required in the future to address the methodological limitations identified in this review. Systematic Review Registration Identifier INPLASY2022100104.
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Affiliation(s)
- Yuanchen Lv
- 1st Clinical Department, China Medical University, Shenyang, Liaoning, China
| | - Zibo Hua
- 1st Clinical Department, China Medical University, Shenyang, Liaoning, China
| | - Xiaomei Lu
- Department of Pathophysiology, College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning, China
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Zhou L, Gong L, Liu Z, Xiang J, Ren C, Xu Y. Probiotic interventions with highly acid-tolerant Levilactobacillus brevis strains improve lipid metabolism and gut microbial balance in obese mice. Food Funct 2025; 16:112-132. [PMID: 39621366 DOI: 10.1039/d4fo03417a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2024]
Abstract
Many studies have shown that specific lactic acid bacteria (LAB) strains can delay obesity, offering a viable alternative to medications and surgeries. However, the mining and development of highly effective LAB strains for obesity control is still limited. In this study, the naturally highly acid-tolerant and gamma-aminobutyric acid-producing Levilactobacillus brevis D17 and its glnR deletion strain were used to investigate their anti-obesity effects. In an 8-week mouse experiment, L. brevis D17 and its glnR-deletion strain D17ΔglnR significantly reduced weight gain by 28.4% and 29.1%, respectively, improving abnormal serum indicators and glucose metabolism caused by a high-fat diet. Furthermore, L. brevis D17 and its glnR-deletion strain D17ΔglnR successfully colonized in the gut. Both D17 and D17ΔglnR interventions significantly restored the relative abundance of Muribaculaceae, Ileibacterium valens, Lactobacillus, Faecalibaculum, Bifidobacterium globosum, Akkermansia muciniphila, and Romboutsia ilealis, whereas they significantly reduced potentially harmful bacteria like Leptogranulimonas, Flintibacter, and Alistipes. Additionally, L. brevis intervention effectively decreased the levels of primary bile acids and increased secondary bile acids in the gut, thus balancing bile acid metabolism. The transcriptional analysis suggested that D17 and D17ΔglnR interventions may activate the AMPK signaling pathway in the liver to inhibit lipogenesis, activate the cAMP pathway to promote lipolysis, and inhibit pro-inflammatory macrophage infiltration to block inflammatory responses. These results indicate that L. brevis D17 and its glnR-deletion mutant strain D17ΔglnR show great potential in combating obesity. Moreover, these results also provide insights into the underlying mechanism behind their anti-obesity properties.
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Affiliation(s)
- Liping Zhou
- Lab of Brewing Microbiology and Applied Enzymology, Key Laboratory of Industrial Biotechnology of Ministry of Education, Jiangnan University, Wuxi, China.
| | - Luchan Gong
- Lab of Brewing Microbiology and Applied Enzymology, Key Laboratory of Industrial Biotechnology of Ministry of Education, Jiangnan University, Wuxi, China.
| | - Zhihao Liu
- Lab of Brewing Microbiology and Applied Enzymology, Key Laboratory of Industrial Biotechnology of Ministry of Education, Jiangnan University, Wuxi, China.
| | - Jinfeng Xiang
- Lab of Brewing Microbiology and Applied Enzymology, Key Laboratory of Industrial Biotechnology of Ministry of Education, Jiangnan University, Wuxi, China.
| | - Cong Ren
- Lab of Brewing Microbiology and Applied Enzymology, Key Laboratory of Industrial Biotechnology of Ministry of Education, Jiangnan University, Wuxi, China.
- China Key Laboratory of Microbiomics and Eco-brewing Technology for Light Industry, Wuxi 214122, Jiangsu, China
| | - Yan Xu
- Lab of Brewing Microbiology and Applied Enzymology, Key Laboratory of Industrial Biotechnology of Ministry of Education, Jiangnan University, Wuxi, China.
- China Key Laboratory of Microbiomics and Eco-brewing Technology for Light Industry, Wuxi 214122, Jiangsu, China
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Sun J, Shi M, Mei R, Zhao Y, Huang Y, Song Z, Hua F, Zhang M, Liu J. LincR-PPP2R5C regulates the PP2A signaling pathway in the macrophage-myofibroblast transition in a mouse model of epidural fibrosis. Mol Immunol 2025; 177:85-95. [PMID: 39729722 DOI: 10.1016/j.molimm.2024.12.006] [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: 09/15/2024] [Revised: 11/18/2024] [Accepted: 12/23/2024] [Indexed: 12/29/2024]
Abstract
Low back pain after spine surgery is a major complication due to excessive epidural fibrosis, which compresses the lumbar nerve. Macrophage-myofibroblast transition (MMT) promoted epidural fibrosis in a mouse laminectomy model. Previously, we demonstrated that LincR-PPP2R5C regulated CD4 + T-cell differentiation. Here, we aimed to explore the roles and mechanisms of LincR-PPP2R5C in macrophages in epidural fibrosis. In M2 macrophages, the level of LincR-PPP2R5C was significantly decreased. Upon overexpression, LincR-PPP2R5C induced M1-macrophage polarization and reduced MMT. In contrast, LincR-PPP2R5C deficiency promoted M2-macrophage polarization and increased MMT. Mechanistically, LincR-PPP2R5C modulated the expression of α-SMA in macrophages via the PP2A signaling pathway. In vivo, LincR-PPP2R5C deficiency aggravated epidural fibrosis by enhancing MMT in a mouse model of laminectomy, and this effect was abolished in mice with macrophage depletion. Our study shed light on the effects of LincR-PPP2R5C on macrophage differentiation and MMT in epidural fibrosis.
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Affiliation(s)
- Jinpeng Sun
- Department of Orthopedics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Mohan Shi
- Department of Orthopedics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Rui Mei
- Department of Orthopedics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Youpeng Zhao
- Department of Orthopedics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yue Huang
- Department of Orthopedics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zeyuan Song
- Department of Orthopedics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Feng Hua
- Department of Orthopedics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Mingshun Zhang
- NHC Key Laboratory of Antibody Technique, Jiangsu Province Engineering Research Center of Antibody Drug, Department of Immunology, Nanjing Medical University, Nanjing, China.
| | - Jun Liu
- Department of Orthopedics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.
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34
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Janosevic D, De Luca T, Eadon MT. The Kidney Precision Medicine Project and Single-Cell Biology of the Injured Proximal Tubule. THE AMERICAN JOURNAL OF PATHOLOGY 2025; 195:7-22. [PMID: 39332674 PMCID: PMC11686451 DOI: 10.1016/j.ajpath.2024.09.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 08/29/2024] [Accepted: 09/11/2024] [Indexed: 09/29/2024]
Abstract
Single-cell RNA sequencing (scRNA-seq) has led to major advances in our understanding of proximal tubule subtypes in health and disease. The proximal tubule serves essential functions in overall homeostasis, but pathologic or physiological perturbations can affect its transcriptomic signature and corresponding tasks. These alterations in proximal tubular cells are often described within a scRNA-seq atlas as cell states, which are pathophysiological subclassifications based on molecular and morphologic changes in a cell's response to that injury compared with its native state. This review describes the major cell states defined in the Kidney Precision Medicine Project's scRNA-seq atlas. It then identifies the overlap between the Kidney Precision Medicine Project and other seminal works that may use different nomenclature or cluster proximal tubule cells at different resolutions to define cell state subtypes. The goal is for the reader to understand the key transcriptomic markers of important cellular injury and regeneration processes across this highly dynamic and evolving field.
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Affiliation(s)
- Danielle Janosevic
- Division of Nephrology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Thomas De Luca
- Division of Nephrology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Michael T Eadon
- Division of Nephrology, Indiana University School of Medicine, Indianapolis, Indiana.
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Jia Q, Ding Y, Su Z, Chen H, Ye J, Xie D, Wu Y, He H, Peng Y, Ni Y. Cell membrane-camouflaged nanoparticles activate fibroblast-myofibroblast transition to promote skin wound healing. Biofabrication 2024; 17:015036. [PMID: 39657324 DOI: 10.1088/1758-5090/ad9cc4] [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: 08/27/2024] [Accepted: 12/10/2024] [Indexed: 12/12/2024]
Abstract
The fibroblast-myofibroblast transition marked by extracellular matrix (ECM) secretion and contraction of actomyosin-based stress fibers, plays central roles in the wound healing process. This work aims to utilize the cell membrane-based nanoplatform to improve the outcomes of dysregulated wound healing. The cell membranes of myofibroblasts isolated from mouse skin are used as the camouflage for gold nanoparticles loaded with IL-4 cytokine. The membrane-modified nanoparticles show effective in situ clearance of bacterial infection, and act as the activator in IL-4Rα signaling pathway to induce pro-inflammatory M1 macrophages into the anti-inflammatory M2 phenotype. Thus, the poor bacteria-clearance and non-stop inflammation in refractory wounds are improved and accelerated. Furthermore, the nanoplatform releases myofibroblast membranes to propel primitive fibroblasts toward the fibroblast-myofibroblast transition in an epigenetic manner. Matrix-production, vascularization, and epithelial regeneration are then initiated, leading to the satisfactory wound closure. Our study devises a new strategy for activating fibroblasts into myofibroblasts under prolonged and continuous exposure to the fibrotic environment, and develops a promising biomimetic nanoplatform for effective treatment of dysregulated chronic wound healing.
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Affiliation(s)
- Qi Jia
- The M.O.E. Key Laboratory of Laboratory Medical Diagnostics, The College of Laboratory Medicine, Chongqing Medical University, #1 Yixueyuan Road, Yuzhong District, Chongqing 400016, People's Republic of China
| | - Yijuan Ding
- The M.O.E. Key Laboratory of Laboratory Medical Diagnostics, The College of Laboratory Medicine, Chongqing Medical University, #1 Yixueyuan Road, Yuzhong District, Chongqing 400016, People's Republic of China
| | - Ziwen Su
- The M.O.E. Key Laboratory of Laboratory Medical Diagnostics, The College of Laboratory Medicine, Chongqing Medical University, #1 Yixueyuan Road, Yuzhong District, Chongqing 400016, People's Republic of China
| | - Heying Chen
- The M.O.E. Key Laboratory of Laboratory Medical Diagnostics, The College of Laboratory Medicine, Chongqing Medical University, #1 Yixueyuan Road, Yuzhong District, Chongqing 400016, People's Republic of China
| | - Jialing Ye
- The M.O.E. Key Laboratory of Laboratory Medical Diagnostics, The College of Laboratory Medicine, Chongqing Medical University, #1 Yixueyuan Road, Yuzhong District, Chongqing 400016, People's Republic of China
| | - Dafeng Xie
- The M.O.E. Key Laboratory of Laboratory Medical Diagnostics, The College of Laboratory Medicine, Chongqing Medical University, #1 Yixueyuan Road, Yuzhong District, Chongqing 400016, People's Republic of China
| | - Yubo Wu
- The M.O.E. Key Laboratory of Laboratory Medical Diagnostics, The College of Laboratory Medicine, Chongqing Medical University, #1 Yixueyuan Road, Yuzhong District, Chongqing 400016, People's Republic of China
| | - Haiyan He
- The M.O.E. Key Laboratory of Laboratory Medical Diagnostics, The College of Laboratory Medicine, Chongqing Medical University, #1 Yixueyuan Road, Yuzhong District, Chongqing 400016, People's Republic of China
| | - Yanlin Peng
- The M.O.E. Key Laboratory of Laboratory Medical Diagnostics, The College of Laboratory Medicine, Chongqing Medical University, #1 Yixueyuan Road, Yuzhong District, Chongqing 400016, People's Republic of China
| | - Yilu Ni
- The M.O.E. Key Laboratory of Laboratory Medical Diagnostics, The College of Laboratory Medicine, Chongqing Medical University, #1 Yixueyuan Road, Yuzhong District, Chongqing 400016, People's Republic of China
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Wang K, Zhang L, Deng B, Zhao K, Chen C, Wang W. Mitochondrial uncoupling protein 2: a central player in pancreatic disease pathophysiology. Mol Med 2024; 30:259. [PMID: 39707176 DOI: 10.1186/s10020-024-01027-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Accepted: 12/03/2024] [Indexed: 12/23/2024] Open
Abstract
Pancreatic diseases pose considerable health challenges due to their complex etiology and limited therapeutic options. Mitochondrial uncoupling protein 2 (UCP2), highly expressed in pancreatic tissue, participates in numerous physiological processes and signaling pathways, indicating its potential relevance in these diseases. Despite this, UCP2's role in acute pancreatitis (AP) remains underexplored, and its functions in chronic pancreatitis (CP) and pancreatic steatosis are largely unknown. Additionally, the mechanisms connecting various pancreatic diseases are intricate and not yet fully elucidated. Given UCP2's diverse functionality, broad expression in pancreatic tissue, and the distinct pathophysiological features of pancreatic diseases, this review offers a comprehensive analysis of current findings on UCP2's involvement in these conditions. We discuss recent insights into UCP2's complex regulatory mechanisms, propose that UCP2 may serve as a central regulatory factor in pancreatic disease progression, and hypothesize that UCP2 dysfunction could significantly contribute to disease pathogenesis. Understanding UCP2's role and mechanisms in pancreatic diseases may pave the way for innovative therapeutic and diagnostic approaches.
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Affiliation(s)
- Kunpeng Wang
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, China
- General Surgery Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Lilong Zhang
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, China
- General Surgery Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Beiying Deng
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Kailiang Zhao
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, China
- General Surgery Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Chen Chen
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, China.
- General Surgery Laboratory, Renmin Hospital of Wuhan University, Wuhan, China.
| | - Weixing Wang
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, China.
- General Surgery Laboratory, Renmin Hospital of Wuhan University, Wuhan, China.
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Zhang J, Huang J, Yang Q, Zeng L, Deng K. Regulatory mechanisms of macrophage-myofibroblast transdifferentiation: A potential therapeutic strategy for fibrosis. Biochem Biophys Res Commun 2024; 737:150915. [PMID: 39486135 DOI: 10.1016/j.bbrc.2024.150915] [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: 07/09/2024] [Revised: 10/27/2024] [Accepted: 10/27/2024] [Indexed: 11/04/2024]
Abstract
Macrophage-myofibroblast transdifferentiation (MMT), a fibrotic process impacting diverse tissue types, has garnered recent scholarly interest. Within damaged tissues, the role of myofibroblasts is pivotal in the accumulation of excessive fibrous connective tissue, leading to persistent scarring or organ dysfunction. Consequently, the examination of MMT-related fibrosis is imperative. This review underscores MMT as a fundamental mechanism in myofibroblast generation during tissue fibrosis, and its exploration is crucial for elucidating the regulatory mechanisms underlying this process. Gaining insight into these mechanisms promises to facilitate the development of therapeutic approaches aimed at inhibiting and reversing fibrosis, thereby offering potential avenues for the treatment of fibrotic diseases.
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Affiliation(s)
- Junchao Zhang
- Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Foshan, Guangdong, China
| | - Jinfa Huang
- Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Foshan, Guangdong, China
| | - Qian Yang
- Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Foshan, Guangdong, China
| | - Lingling Zeng
- Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Foshan, Guangdong, China
| | - Kaixian Deng
- Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Foshan, Guangdong, China.
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Jiang Y, Cai R, Huang Y, Zhu L, Xiao L, Wang C, Wang L. Macrophages in organ fibrosis: from pathogenesis to therapeutic targets. Cell Death Discov 2024; 10:487. [PMID: 39632841 PMCID: PMC11618518 DOI: 10.1038/s41420-024-02247-1] [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: 07/25/2024] [Revised: 11/11/2024] [Accepted: 11/13/2024] [Indexed: 12/07/2024] Open
Abstract
Fibrosis, an excessive self-repair response, is an age-related pathological process that universally affects various major organs such as the heart, liver, kidney, and lungs. Continuous accumulation of pathological tissue fibrosis destroys structural integrity and causes loss of function, with consequent organ failure and increased mortality. Although some differences exist in the triggering mechanisms and pathophysiologic manifestations of organ-specific fibrosis, they usually share similar cascading responses and features, including chronic inflammatory stimulation, parenchymal cell injury, and macrophage recruitment. Macrophages, due to their high plasticity, can polarize into different phenotypes in response to varied microenvironments and play a crucial role in the development of organ fibrosis. This review examined the relationship between macrophages and the pathogenesis of organ fibrosis. Moreover, it analyzed how fibrosis can be modulated by targeting macrophages, which may become a novel and promising therapeutic strategy for fibrosis.
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Affiliation(s)
- Yuanyuan Jiang
- Translational Medical Innovation Center, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, 215600, Jiangsu, China
| | - Rong Cai
- Translational Medical Innovation Center, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, 215600, Jiangsu, China
| | - Yu Huang
- Department of Obstetrics and Gynecology, Zhangjiagang Hospital Affiliated to Soochow University, Zhangjiagang, 215600, Jiangsu, China
| | - Like Zhu
- Translational Medical Innovation Center, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, 215600, Jiangsu, China
| | - Long Xiao
- Translational Medical Innovation Center, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, 215600, Jiangsu, China
| | - Caihong Wang
- Translational Medical Innovation Center, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, 215600, Jiangsu, China.
| | - Lihong Wang
- Translational Medical Innovation Center, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, 215600, Jiangsu, China.
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39
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Li J, Yan X, Wu Z, Shen J, Li Y, Zhao Y, Du F, Li M, Wu X, Chen Y, Xiao Z, Wang S. Role of miRNAs in macrophage-mediated kidney injury. Pediatr Nephrol 2024; 39:3397-3410. [PMID: 38801452 DOI: 10.1007/s00467-024-06414-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 04/13/2024] [Accepted: 05/03/2024] [Indexed: 05/29/2024]
Abstract
Macrophages, crucial components of the human immune system, can be polarized into M1/M2 phenotypes, each with distinct functions and roles. Macrophage polarization has been reported to be significantly involved in the inflammation and fibrosis observed in kidney injury. MicroRNA (miRNA), a type of short RNA lacking protein-coding function, can inhibit specific mRNA by partially binding to its target mRNA. The intricate association between miRNAs and macrophages has been attracting increasing interest in recent years. This review discusses the role of miRNAs in regulating macrophage-mediated kidney injury. It shows how miRNAs can influence macrophage polarization, thereby altering the biological function of macrophages in the kidney. Furthermore, this review highlights the significance of miRNAs derived from exosomes and extracellular vesicles as a crucial mediator in the crosstalk between macrophages and kidney cells. The potential of miRNAs as treatment applications and biomarkers for macrophage-mediated kidney injury is also discussed.
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Affiliation(s)
- Junxin Li
- Department of Pharmacy, Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China
- Laboratory of Personalised Cell Therapy and Cell Medicine, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
| | - Xida Yan
- Department of Pharmacy, Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
- Department of Pharmacy, Mianyang Central Hospital, Mianyang, China
| | - Zhigui Wu
- Department of Pharmacy, Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China
- Laboratory of Personalised Cell Therapy and Cell Medicine, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China
- Laboratory of Personalised Cell Therapy and Cell Medicine, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
| | - Yalin Li
- Department of Pharmacy, Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China
- Laboratory of Personalised Cell Therapy and Cell Medicine, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
| | - Fukuan Du
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China
- Laboratory of Personalised Cell Therapy and Cell Medicine, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China
- Laboratory of Personalised Cell Therapy and Cell Medicine, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
| | - Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China
- Laboratory of Personalised Cell Therapy and Cell Medicine, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
| | - Yu Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China
- Laboratory of Personalised Cell Therapy and Cell Medicine, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
| | - Zhangang Xiao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China
- Laboratory of Personalised Cell Therapy and Cell Medicine, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
| | - Shurong Wang
- Department of Pharmacy, Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China.
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40
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Bøgh N, Bertelsen LB, Rasmussen CW, Bech SK, Keller AK, Madsen MG, Harving F, Thorsen TH, Mieritz IK, Hansen ES, Wanders A, Laustsen C. Metabolic MRI With Hyperpolarized 13 C-Pyruvate for Early Detection of Fibrogenic Kidney Metabolism. Invest Radiol 2024; 59:813-822. [PMID: 38913443 DOI: 10.1097/rli.0000000000001094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/26/2024]
Abstract
OBJECTIVES Fibrosis is the final common pathway for chronic kidney disease and the best predictor for disease progression. Besides invasive biopsies, biomarkers for its detection are lacking. To address this, we used hyperpolarized 13 C-pyruvate MRI to detect the metabolic changes associated with fibrogenic activity of myofibroblasts. MATERIALS AND METHODS Hyperpolarized 13 C-pyruvate MRI was performed in 2 pig models of kidney fibrosis (unilateral ureteral obstruction and ischemia-reperfusion injury). The imaging data were correlated with histology, biochemical, and genetic measures of metabolism and fibrosis. The porcine experiments were supplemented with cell-line experiments to inform the origins of metabolic changes in fibrogenesis. Lastly, healthy and fibrotic human kidneys were analyzed for the metabolic alterations accessible with hyperpolarized 13 C-pyruvate MRI. RESULTS In the 2 large animal models of kidney fibrosis, metabolic imaging revealed alterations in amino acid metabolism and glycolysis. Conversion from hyperpolarized 13 C-pyruvate to 13 C-alanine decreased, whereas conversion to 13 C-lactate increased. These changes were shown to reflect profibrotic activity in cultured epithelial cells, macrophages, and fibroblasts, which are important precursors of myofibroblasts. Importantly, metabolic MRI using hyperpolarized 13 C-pyruvate was able to detect these changes earlier than fibrosis-sensitive structural imaging. Lastly, we found that the same metabolic profile is present in fibrotic tissue from human kidneys. This affirms the translational potential of metabolic MRI as an early indicator of fibrogenesis associated metabolism. CONCLUSIONS Our findings demonstrate the promise of hyperpolarized 13 C-pyruvate MRI for noninvasive detection of fibrosis development, which could enable earlier diagnosis and intervention for patients at risk of kidney fibrosis.
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Affiliation(s)
- Nikolaj Bøgh
- From the MR Research Center, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark (N.B., L.B.B., C.W.R., S.K.B., T.H.T., I.K.M., E.S.S.H., C.L.); Department of Urology, Aarhus University Hospital, Aarhus, Denmark (A.K.K., M.G.M.); and Department of Pathology, Aalborg University Hospital, Aalborg, Denmark (F.H., A.W.)
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Yu W, Song J, Chen S, Nie J, Zhou C, Huang J, Liang H. Myofibroblast-derived exosomes enhance macrophages to myofibroblasts transition and kidney fibrosis. Ren Fail 2024; 46:2334406. [PMID: 38575341 PMCID: PMC10997357 DOI: 10.1080/0886022x.2024.2334406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/06/2024] Open
Abstract
A critical event in the pathogenesis of kidney fibrosis is the transition of macrophages into myofibroblasts (MMT). Exosomes play an important role in crosstalk among cells in the kidney and the development of renal fibrosis. However, the role of myofibroblast-derived exosomes in the process of MMT and renal fibrosis progression remains unknown. Here, we examined the role of myofibroblast-derived exosomes in MMT and kidney fibrogenesis. In vitro, transforming growth factor-β1 stimulated the differentiation of kidney fibroblasts into myofibroblasts and promoted exosome release from myofibroblasts. RAW264.7 cells were treated with exosomes derived from myofibroblasts. We found purified exosomes from myofibroblasts trigger the MMT. By contrast, inhibition of exosome production with GW4869 or exosome depletion from the conditioned media abolished the ability of myofibroblasts to induce MMT. Mice treatment with myofibroblast-derived exosomes (Myo-Exo) exhibited severe fibrotic lesion and more abundant MMT cells in kidneys with folic acid (FA) injury, which was negated by TANK-banding kinase-1 inhibitor. Furthermore, suppression of exosome production reduced collagen deposition, extracellular matrix protein accumulation, and MMT in FA nephropathy. Collectively, Myo-Exo enhances the MMT and kidney fibrosis. Blockade of exosomes mediated myofibroblasts-macrophages communication may provide a novel therapeutic target for kidney fibrosis.
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Affiliation(s)
- Wenqiang Yu
- Department of Anesthesiology, Foshan Women and Children Hospital, Foshan, China
| | - Jinfang Song
- Zhuhai Campus, Zunyi Medical University, Zhuhai, China
| | - Shuangquan Chen
- Department of Anesthesiology, Foshan Women and Children Hospital, Foshan, China
| | - Jiayi Nie
- Department of Anesthesiology, Foshan Women and Children Hospital, Foshan, China
| | - Chujun Zhou
- Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Jiamin Huang
- Department of Anesthesiology, Foshan Women and Children Hospital, Foshan, China
| | - Hua Liang
- Department of Anesthesiology, Foshan Women and Children Hospital, Foshan, China
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Guo Q, Li P, Chen M, Yu Y, Wan Y, Zhang Z, Ren C, Shen L, Liu X, He D, Zhang Y, Wei G, Zhang D. Exosomes From Human Umbilical Cord Stem Cells Suppress Macrophage-to-myofibroblast Transition, Alleviating Renal Fibrosis. Inflammation 2024; 47:2094-2107. [PMID: 38662165 DOI: 10.1007/s10753-024-02027-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 04/10/2024] [Accepted: 04/12/2024] [Indexed: 04/26/2024]
Abstract
Renal fibrosis, a progressive scarring of the kidney, lacks effective treatment. Human umbilical cord mesenchymal stem cell-derived exosomes (HucMSC-Exos) hold promise for treating kidney diseases due to their anti-inflammatory properties. This study investigates their potential to lessen renal fibrosis by targeting macrophage-to-myofibroblast transformation (MMT), a key driver of fibrosis. We employed a mouse model of unilateral ureteral obstruction (UUO) and cultured cells exposed to transforming growth factor-β (TGF-β) to mimic MMT. HucMSC-Exos were administered to UUO mice, and their effects on kidney function and fibrosis were assessed. Additionally, RNA sequencing and cellular analysis were performed to elucidate the mechanisms by which HucMSC-Exos inhibit MMT. HucMSC-Exos treatment significantly reduced kidney damage and fibrosis in UUO mice. They downregulated markers of fibrosis (Collagen I, vimentin, alpha-smooth muscle actin) and suppressed MMT (α-SMA + F4/80 + cells). Furthermore, ARNTL, a specific molecule, emerged as a potential target of HucMSC-Exos in hindering MMT and consequently preventing fibrosis. HucMSC-Exos effectively lessen renal fibrosis by suppressing MMT, suggesting a novel therapeutic strategy for managing kidney damage and fibrosis.
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Affiliation(s)
- Qitong Guo
- Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China
- National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Chongqing Key Laboratory of Structural Birth Defect and Reconstruction, Chongqing, 400014, China
| | - Ping Li
- Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China
- National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Chongqing Key Laboratory of Structural Birth Defect and Reconstruction, Chongqing, 400014, China
| | - Meiling Chen
- Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China
- National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Chongqing Key Laboratory of Structural Birth Defect and Reconstruction, Chongqing, 400014, China
| | - Yihang Yu
- Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China
- National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Chongqing Key Laboratory of Structural Birth Defect and Reconstruction, Chongqing, 400014, China
| | - Yonghong Wan
- Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China
- National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Chongqing Key Laboratory of Structural Birth Defect and Reconstruction, Chongqing, 400014, China
| | - Zhaoxia Zhang
- Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China
- National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Chongqing Key Laboratory of Structural Birth Defect and Reconstruction, Chongqing, 400014, China
| | - Chunnian Ren
- Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China
- National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Chongqing Key Laboratory of Structural Birth Defect and Reconstruction, Chongqing, 400014, China
| | - Lianju Shen
- Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China
- National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Chongqing Key Laboratory of Structural Birth Defect and Reconstruction, Chongqing, 400014, China
| | - Xing Liu
- Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China
- National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Chongqing Key Laboratory of Structural Birth Defect and Reconstruction, Chongqing, 400014, China
| | - Dawei He
- Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China
- National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Chongqing Key Laboratory of Structural Birth Defect and Reconstruction, Chongqing, 400014, China
| | - Yuanyuan Zhang
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, 27101, USA
| | - Guanghui Wei
- Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China
- National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Chongqing Key Laboratory of Structural Birth Defect and Reconstruction, Chongqing, 400014, China
| | - Deying Zhang
- Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.
- National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Chongqing Key Laboratory of Structural Birth Defect and Reconstruction, Chongqing, 400014, China.
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Hu Y, Wang Y, Hong H, Chen Y, Zhou Q, Zhu G, Tang J, Liu W, Wang L. Global trends and prospects related to macrophage in chronic kidney disease: a bibliometric analysis. Ren Fail 2024; 46:2423846. [PMID: 39572163 PMCID: PMC11583328 DOI: 10.1080/0886022x.2024.2423846] [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: 08/04/2024] [Revised: 10/11/2024] [Accepted: 10/27/2024] [Indexed: 11/24/2024] Open
Abstract
BACKGROUND AND AIMS Macrophages play a variety of widely concerned roles in the process of chronic kidney disease (CKD). To further understand the research hotspots and development trends regarding the relationship between macrophages and CKD, the role of macrophages in the occurrence and progression of CKD was summarized by bibliometrics in this study. MATERIAL AND METHODS We collected the studies relevant the role of macrophages in CKD from the Web of Science Core Collection, which included 1332 relevant studies from Jan 1st, 2004 to Jul 6th, 2023 in WoSCC. CiteSpace, biblioshiny in R, VOSviewer and SCImago Graphica Beta were used for bibliometric analysis and visualization. RESULTS Monash University from Australia is the most productive institution, while China and the USA are most productive countries. Anders HJ is the most cited author. In terms of the number of co-citations, the top one was "Macrophages: versatile players in renal inflammation and fibrosis" by Patrick Ming-Kuen Tang, published in Nature Reviews Nephrology in 2019. Important keywords of this research topic include inflammation, dendritic cell, oxidative stress, NF-κB, tgf-beta, interstitial fibrosis, glomerulonephritis, diabetic nephropathy. Future research hotspots may include molecular mechanism, acute kidney injury, macrophage polarization, kidney fibrosis. CONCLUSION This study provides a systematic review of the role of macrophages in CKD and speculates that future research hotspots. Previous studies have focused on the immune function of macrophages and atypia, and metabolic factors (especially iron metabolism within macrophages) have attracted the attention of researchers in recent years and are the forefront of recent research.
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Affiliation(s)
- Yuxin Hu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
- Renal Research-Institution of Beijing University of Chinese Medicine, Beijing, China
| | - Yaoxian Wang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Renal Research-Institution of Beijing University of Chinese Medicine, Beijing, China
- Henan University of Chinese Medicine, Henan, China
| | - Hanzhang Hong
- Beijing University of Chinese Medicine, Beijing, China
| | - Yexin Chen
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
| | - Qinjie Zhou
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
| | | | - Jingyi Tang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
- Renal Research-Institution of Beijing University of Chinese Medicine, Beijing, China
| | - Weijing Liu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Lin Wang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Renal Research-Institution of Beijing University of Chinese Medicine, Beijing, China
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Affiliated to Beijing University of Chinese Medicine, Beijing, China
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Zeng J, Du XL, Lu QQ, Chen WQ, Yang XJ. Inhibition of GDNF-Driven Macrophage-to-Myofibroblast Transition Protects Against Colitis-Associated Intestinal Fibrosis. Inflammation 2024. [DOI: 10.1007/s10753-024-02175-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 10/03/2024] [Accepted: 10/27/2024] [Indexed: 01/03/2025]
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45
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Zuo YB, Wen ZJ, Cheng MD, Jia DD, Zhang YF, Yang HY, Xu HM, Xin H, Zhang YF. The pro-atherogenic effects and the underlying mechanisms of chronic bisphenol S (BPS) exposure in apolipoprotein E-deficient mice. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2024; 285:117133. [PMID: 39342757 DOI: 10.1016/j.ecoenv.2024.117133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 07/23/2024] [Accepted: 09/26/2024] [Indexed: 10/01/2024]
Abstract
Atherosclerosis (AS) and its related cardiovascular diseases (CVDs) remain the most frequent cause of morbidity and mortality worldwide. Researches showed that bisphenol A (BPA) exposure might exacerbate AS progression. However, as an analogue of BPA, little is known about the cardiovascular toxicity of bisphenol S (BPS), especially whether BPS exposure has the pro-atherogenic effects in mammals is still unknown. Here, we firstly constructed an apolipoprotein E knockout (ApoE-/-) mouse model and cultured cells to investigate the risk of BPS on AS and explore the underlying mechanisms. Results showed that prolonged exposure to 50 μg/kg body weight (bw)/day BPS indeed aggravated AS lesions both in the en face aortas and aortic sinuses of ApoE-/- mice. Moreover, BPS were found to be implicated in the AS pathological process: 1) stimulates adhesion molecule expression to promote monocyte-endothelial cells (ECs) adhesion with 3.6 times more than the control group in vivo; 2) increases the distribution of vascular smooth muscle cells (VSMCs) with 9.3 times more than the control group in vivo, possibly through the migration of VSMCs; and 3) induces an inflammatory response by increasing the number of macrophages (MACs), with 3.7 times more than the control group in vivo, and the release of inflammatory mediators. Furthermore, we have identified eight significant AS-related genes induced by BPS, including angiopoietin-like protein 7 (Angptl17) and lipocalin-2 (Lcn2) in ECs; matrix metalloproteinase 9 (Mmp13), secreted phosphoprotein 1 (Spp1), and collagen type II alpha 1 (Col2a1) in VSMCs; and kininogen 1 (Kng1), integrin alpha X (Itgax), and MAC-expressed gene 1 (Mpeg1) in MACs. Overall, this study firstly found BPS exposure could exacerbate mammalian AS and might also provide a theoretical basis for elucidating BPS and its analogues induced AS and related CVDs.
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Affiliation(s)
- Ying-Bing Zuo
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Deng Zhou Road 38, Qingdao 266021, China; Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao University, 16 Jiangsu Road, Qingdao 266000, China
| | - Zeng-Jin Wen
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Deng Zhou Road 38, Qingdao 266021, China
| | - Meng-Die Cheng
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Deng Zhou Road 38, Qingdao 266021, China; Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao University, 16 Jiangsu Road, Qingdao 266000, China
| | - Dong-Dong Jia
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Deng Zhou Road 38, Qingdao 266021, China
| | - Yi-Fei Zhang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Deng Zhou Road 38, Qingdao 266021, China
| | - Hong-Yu Yang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Deng Zhou Road 38, Qingdao 266021, China
| | - Hai-Ming Xu
- School of Public Health, Ningxia Medical University, Yinchuan, Ningxia 750004, China.
| | - Hui Xin
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao University, 16 Jiangsu Road, Qingdao 266000, China.
| | - Yin-Feng Zhang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Deng Zhou Road 38, Qingdao 266021, China.
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Ban JQ, Ao LH, He X, Zhao H, Li J. Advances in macrophage-myofibroblast transformation in fibrotic diseases. Front Immunol 2024; 15:1461919. [PMID: 39445007 PMCID: PMC11496091 DOI: 10.3389/fimmu.2024.1461919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 09/26/2024] [Indexed: 10/25/2024] Open
Abstract
Macrophage-myofibroblast transformation (MMT) has emerged as a discovery in the field of fibrotic disease research. MMT is the process by which macrophages differentiate into myofibroblasts, leading to organ fibrosis following organ damage and playing an important role in fibrosis formation and progression. Recently, many new advances have been made in studying the mechanisms of MMT occurrence in fibrotic diseases. This article reviews some critical recent findings on MMT, including the origin of MMT in myofibroblasts, the specific mechanisms by which MMT develops, and the mechanisms and effects of MMT in the kidneys, lungs, heart, retina, and other fibrosis. By summarizing the latest research related to MMT, this paper provides a theoretical basis for elucidating the mechanisms of fibrosis in various organs and developing effective therapeutic targets for fibrotic diseases.
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Affiliation(s)
| | | | | | | | - Jun Li
- School of Public Health, the Key Laboratory of Environmental Pollution Monitoring and
Disease Control, Ministry of Education, Guizhou Medical University,
Guiyang, China
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47
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Liu T, Zhang Y, Wu Z, Zhao CJ, Dong X, Gong HX, Jin B, Han MM, Wu JJ, Fan YK, Li N, Xiong YX, Zhang ZQ, Dong ZQ. Novel glucomannan-like polysaccharide from Lycium barbarum L. ameliorates renal fibrosis via blocking macrophage-to-myofibroblasts transition. Int J Biol Macromol 2024; 278:134491. [PMID: 39111495 DOI: 10.1016/j.ijbiomac.2024.134491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 07/18/2024] [Accepted: 08/02/2024] [Indexed: 08/26/2024]
Abstract
The macrophage to myofibroblasts transition (MMT) has been reported as a newly key target in renal fibrosis. Lycium barbarum L. is a traditional Chinese medicine for improving renal function, in which its polysaccharides (LBPs) are the mainly active components. However, whether the role of LBPs in treating renal fibrosis is related to MMT process remain unclear. The purpose of this study was to explore the relationship between the regulating effect on MMT process and the anti-fibrotic effect of LBPs. Initially, small molecular weight LBPs fractions (LBP-S) were firstly isolated via Sephadex G-100 column. Then, the potent inhibitory effect of LBP-S on MMT process was revealed on bone marrow-derived macrophages (BMDM) model induced by TGF-β. Subsequently, the chemical structure of LBP-S was elucidated through monosaccharide, methylation and NMR spectrum analysis. In vivo biodistribution characteristics studies demonstrated that LBP-S exhibited effectively accumulation in kidney via intraperitoneal administration. Finally, LBP-S showed a satisfactory anti-renal fibrotic effect on unilateral ureteral obstruction operation (UUO) mice, which was significantly reduced following macrophage depletion. Overall, our findings indicated that LPB-S could alleviate renal fibrosis through regulating MMT process and providing new candidate agents for chronic kidney disease (CKD) related fibrosis treatment.
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Affiliation(s)
- Tian Liu
- IMPLAD, Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine from Ministry of Education, CAMS, Beijing 100193, China; IMPLAD, Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, CAMS, Beijing 100193, China
| | - Yun Zhang
- Institute of Medicinal Plant Development (IMPLAD), State Key Laboratory of Quality Ensurance and Sustainable Use of Dao-Di herbs, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS), Beijing 100193, China; IMPLAD, Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine from Ministry of Education, CAMS, Beijing 100193, China
| | - Ze Wu
- Institute of Medicinal Plant Development (IMPLAD), State Key Laboratory of Quality Ensurance and Sustainable Use of Dao-Di herbs, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS), Beijing 100193, China
| | - Chen-Jing Zhao
- IMPLAD, Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine from Ministry of Education, CAMS, Beijing 100193, China
| | - Xi Dong
- Institute of Medicinal Plant Development (IMPLAD), State Key Laboratory of Quality Ensurance and Sustainable Use of Dao-Di herbs, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS), Beijing 100193, China
| | - He-Xin Gong
- Institute of Medicinal Plant Development (IMPLAD), State Key Laboratory of Quality Ensurance and Sustainable Use of Dao-Di herbs, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS), Beijing 100193, China
| | - Bing Jin
- Institute of Medicinal Plant Development (IMPLAD), State Key Laboratory of Quality Ensurance and Sustainable Use of Dao-Di herbs, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS), Beijing 100193, China
| | - Miao-Miao Han
- Institute of Medicinal Plant Development (IMPLAD), State Key Laboratory of Quality Ensurance and Sustainable Use of Dao-Di herbs, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS), Beijing 100193, China
| | - Jin-Jia Wu
- Institute of Medicinal Plant Development (IMPLAD), State Key Laboratory of Quality Ensurance and Sustainable Use of Dao-Di herbs, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS), Beijing 100193, China
| | - Yi-Kai Fan
- Institute of Medicinal Plant Development (IMPLAD), State Key Laboratory of Quality Ensurance and Sustainable Use of Dao-Di herbs, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS), Beijing 100193, China
| | - Nan Li
- Institute of Medicinal Plant Development (IMPLAD), State Key Laboratory of Quality Ensurance and Sustainable Use of Dao-Di herbs, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS), Beijing 100193, China
| | - Ying-Xia Xiong
- Institute of Medicinal Plant Development (IMPLAD), State Key Laboratory of Quality Ensurance and Sustainable Use of Dao-Di herbs, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS), Beijing 100193, China
| | - Zi-Qian Zhang
- Institute of Medicinal Plant Development (IMPLAD), State Key Laboratory of Quality Ensurance and Sustainable Use of Dao-Di herbs, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS), Beijing 100193, China
| | - Zheng-Qi Dong
- Institute of Medicinal Plant Development (IMPLAD), State Key Laboratory of Quality Ensurance and Sustainable Use of Dao-Di herbs, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS), Beijing 100193, China; IMPLAD, Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine from Ministry of Education, CAMS, Beijing 100193, China.
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Owen MC, Kopecky BJ. Targeting Macrophages in Organ Transplantation: A Step Toward Personalized Medicine. Transplantation 2024; 108:2045-2056. [PMID: 38467591 PMCID: PMC11390981 DOI: 10.1097/tp.0000000000004978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/13/2024]
Abstract
Organ transplantation remains the most optimal strategy for patients with end-stage organ failure. However, prevailing methods of immunosuppression are marred by adverse side effects, and allograft rejection remains common. It is imperative to identify and comprehensively characterize the cell types involved in allograft rejection, and develop therapies with greater specificity. There is increasing recognition that processes mediating allograft rejection are the result of interactions between innate and adaptive immune cells. Macrophages are heterogeneous innate immune cells with diverse functions that contribute to ischemia-reperfusion injury, acute rejection, and chronic rejection. Macrophages are inflammatory cells capable of innate allorecognition that strengthen their responses to secondary exposures over time via "trained immunity." However, macrophages also adopt immunoregulatory phenotypes and may promote allograft tolerance. In this review, we discuss the roles of macrophages in rejection and tolerance, and detail how macrophage plasticity and polarization influence transplantation outcomes. A comprehensive understanding of macrophages in transplant will guide future personalized approaches to therapies aimed at facilitating tolerance or mitigating the rejection process.
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Affiliation(s)
- Macee C Owen
- Division of Cardiology, Department of Medicine, Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, MI
| | - Benjamin J Kopecky
- Division of Cardiology, Department of Medicine, Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, MI
- Department of Medicine, Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, CO
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Chen C, Feng C, Luo Q, Zeng Y, Yuan W, Cui Y, Tang Z, Zhang H, Li T, Peng J, Peng L, Xie X, Guo Y, Peng F, Jiang X, Bai P, Qi Z, Dai H. CD5L up-regulates the TGF-β signaling pathway and promotes renal fibrosis. Life Sci 2024; 354:122945. [PMID: 39127319 DOI: 10.1016/j.lfs.2024.122945] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 07/25/2024] [Accepted: 08/04/2024] [Indexed: 08/12/2024]
Abstract
Renal fibrosis is the common final pathway of progressive renal diseases, in which the macrophages play an important role. ELISA was used to detect CD5 antigen-like (CD5L) in serum samples from end-stage renal disease (ESRD), as well as in mice serum with unilateral ureteral occlusion (UUO). Recombinant CD5L was injected into UUO mice to assess renal injury, fibrosis, and macrophage infiltration. The expression of CD5L was significantly upregulated in the serum of patients with ESRD and UUO mice. Histological analysis showed that rCD5L-treated UUO mice had more severe renal injury and fibrosis. Furthermore, rCD5L promoted the phenotypic transfer of monocytes from Ly6Chigh to LyC6low. RCD5L promoted TGF-β signaling pathway activation by promoting Smad2/3 phosphorylation. We used Co-IP to identify HSPA5 interact with CD5L on cell membrane could inhibit the formation of the Cripto/HSPA5 complex, and promote the activation of the TGF-β signaling pathway. The CD5L antibody could reduce the degree of renal fibrosis in UUO mice.
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Affiliation(s)
- Chao Chen
- Medical College, Guangxi University, Nanning 530004, China; Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Chen Feng
- Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Qiulin Luo
- Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Yingqi Zeng
- Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Wenjia Yuan
- Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Yan Cui
- Medical College, Guangxi University, Nanning 530004, China; Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Zhouqi Tang
- Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Hedong Zhang
- Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Tengfang Li
- Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Jiawei Peng
- Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Longkai Peng
- Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Xubiao Xie
- Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Yong Guo
- Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Fenghua Peng
- Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Xin Jiang
- Department of Organ Transplantation, The Fifth Clinical Medical College of Henan University of Chinese Medicine (Zhengzhou People's Hospital), Zhengzhou, Henan 450000, China
| | - Peiming Bai
- Medical College, Guangxi University, Nanning 530004, China; Department of Urology, Zhongshan Hospital Xiamen University, Xiamen 361000, China.
| | - Zhongquan Qi
- Medical College, Guangxi University, Nanning 530004, China; Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian 350001, China.
| | - Helong Dai
- Medical College, Guangxi University, Nanning 530004, China; Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China.
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50
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Li X, Liu Y, Tang Y, Xia Z. Transformation of macrophages into myofibroblasts in fibrosis-related diseases: emerging biological concepts and potential mechanism. Front Immunol 2024; 15:1474688. [PMID: 39386212 PMCID: PMC11461261 DOI: 10.3389/fimmu.2024.1474688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Accepted: 09/06/2024] [Indexed: 10/12/2024] Open
Abstract
Macrophage-myofibroblast transformation (MMT) transforms macrophages into myofibroblasts in a specific inflammation or injury microenvironment. MMT is an essential biological process in fibrosis-related diseases involving the lung, heart, kidney, liver, skeletal muscle, and other organs and tissues. This process consists of interacting with various cells and molecules and activating different signal transduction pathways. This review deeply discussed the molecular mechanism of MMT, clarified crucial signal pathways, multiple cytokines, and growth factors, and formed a complex regulatory network. Significantly, the critical role of transforming growth factor-β (TGF-β) and its downstream signaling pathways in this process were clarified. Furthermore, we discussed the significance of MMT in physiological and pathological conditions, such as pulmonary fibrosis and cardiac fibrosis. This review provides a new perspective for understanding the interaction between macrophages and myofibroblasts and new strategies and targets for the prevention and treatment of MMT in fibrotic diseases.
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Affiliation(s)
- Xiujun Li
- Health Science Center, Chifeng University, Chifeng, China
| | - Yuyan Liu
- Rehabilitation Medicine College, Shandong Second Medical University, Jinan, China
| | - Yongjun Tang
- Department of Emergency, Affiliated Hospital of Chifeng University, Chifeng, China
| | - Zhaoyi Xia
- Department of Library, Children’s Hospital Affiliated to Shandong University, Jinan, China
- Department of Library, Jinan Children’s Hospital, Jinan, China
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