Myeloid PFKFB3-mediated glycolysis promotes kidney fibrosis
Excessive renal fibrosis is a common pathology in progressive chronic kidney diseases. Inflammatory injury and aberrant repair processes contribute to the development of kidney fibrosis. Myeloid cells, particularly monocytes/macrophages, play a crucial role in kidney fibrosis by releasing their proi...
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| Format: | Article |
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Frontiers Media S.A.
2023-11-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1259434/full |
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| author | Qiuhua Yang Emily Huo Emily Huo Yongfeng Cai Zhidan Zhang Charles Dong John M. Asara Huidong Shi Huidong Shi Qingqing Wei |
| author_facet | Qiuhua Yang Emily Huo Emily Huo Yongfeng Cai Zhidan Zhang Charles Dong John M. Asara Huidong Shi Huidong Shi Qingqing Wei |
| author_sort | Qiuhua Yang |
| collection | DOAJ |
| description | Excessive renal fibrosis is a common pathology in progressive chronic kidney diseases. Inflammatory injury and aberrant repair processes contribute to the development of kidney fibrosis. Myeloid cells, particularly monocytes/macrophages, play a crucial role in kidney fibrosis by releasing their proinflammatory cytokines and extracellular matrix components such as collagen and fibronectin into the microenvironment of the injured kidney. Numerous signaling pathways have been identified in relation to these activities. However, the involvement of metabolic pathways in myeloid cell functions during the development of renal fibrosis remains understudied. In our study, we initially reanalyzed single-cell RNA sequencing data of renal myeloid cells from Dr. Denby’s group and observed an increased gene expression in glycolytic pathway in myeloid cells that are critical for renal inflammation and fibrosis. To investigate the role of myeloid glycolysis in renal fibrosis, we utilized a model of unilateral ureteral obstruction in mice deficient of Pfkfb3, an activator of glycolysis, in myeloid cells (Pfkfb3ΔMϕ) and their wild type littermates (Pfkfb3WT). We observed a significant reduction in fibrosis in the obstructive kidneys of Pfkfb3ΔMϕ mice compared to Pfkfb3WT mice. This was accompanied by a substantial decrease in macrophage infiltration, as well as a decrease of M1 and M2 macrophages and a suppression of macrophage to obtain myofibroblast phenotype in the obstructive kidneys of Pfkfb3ΔMϕ mice. Mechanistic studies indicate that glycolytic metabolites stabilize HIF1α, leading to alterations in macrophage phenotype that contribute to renal fibrosis. In conclusion, our study implicates that targeting myeloid glycolysis represents a novel approach to inhibit renal fibrosis. |
| first_indexed | 2024-03-11T10:12:38Z |
| format | Article |
| id | doaj.art-41c7ef26380f4bee9e65db688e1798c8 |
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| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-11T10:12:38Z |
| publishDate | 2023-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-41c7ef26380f4bee9e65db688e1798c82023-11-16T14:16:45ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-11-011410.3389/fimmu.2023.12594341259434Myeloid PFKFB3-mediated glycolysis promotes kidney fibrosisQiuhua Yang0Emily Huo1Emily Huo2Yongfeng Cai3Zhidan Zhang4Charles Dong5John M. Asara6Huidong Shi7Huidong Shi8Qingqing Wei9Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, United StatesDepartment of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, United StatesAugusta Preparatory Day School, Martinez, GA, United StatesDepartment of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, United StatesDepartment of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, United StatesDental College of Georgia, Augusta University, Augusta, GA, United StatesDivision of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA, United StatesDepartment of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, United StatesGeorgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, United StatesDepartment of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, United StatesExcessive renal fibrosis is a common pathology in progressive chronic kidney diseases. Inflammatory injury and aberrant repair processes contribute to the development of kidney fibrosis. Myeloid cells, particularly monocytes/macrophages, play a crucial role in kidney fibrosis by releasing their proinflammatory cytokines and extracellular matrix components such as collagen and fibronectin into the microenvironment of the injured kidney. Numerous signaling pathways have been identified in relation to these activities. However, the involvement of metabolic pathways in myeloid cell functions during the development of renal fibrosis remains understudied. In our study, we initially reanalyzed single-cell RNA sequencing data of renal myeloid cells from Dr. Denby’s group and observed an increased gene expression in glycolytic pathway in myeloid cells that are critical for renal inflammation and fibrosis. To investigate the role of myeloid glycolysis in renal fibrosis, we utilized a model of unilateral ureteral obstruction in mice deficient of Pfkfb3, an activator of glycolysis, in myeloid cells (Pfkfb3ΔMϕ) and their wild type littermates (Pfkfb3WT). We observed a significant reduction in fibrosis in the obstructive kidneys of Pfkfb3ΔMϕ mice compared to Pfkfb3WT mice. This was accompanied by a substantial decrease in macrophage infiltration, as well as a decrease of M1 and M2 macrophages and a suppression of macrophage to obtain myofibroblast phenotype in the obstructive kidneys of Pfkfb3ΔMϕ mice. Mechanistic studies indicate that glycolytic metabolites stabilize HIF1α, leading to alterations in macrophage phenotype that contribute to renal fibrosis. In conclusion, our study implicates that targeting myeloid glycolysis represents a novel approach to inhibit renal fibrosis.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1259434/fullmacrophageglycolysisrenal fibrosisPFKFB3inflammation |
| spellingShingle | Qiuhua Yang Emily Huo Emily Huo Yongfeng Cai Zhidan Zhang Charles Dong John M. Asara Huidong Shi Huidong Shi Qingqing Wei Myeloid PFKFB3-mediated glycolysis promotes kidney fibrosis Frontiers in Immunology macrophage glycolysis renal fibrosis PFKFB3 inflammation |
| title | Myeloid PFKFB3-mediated glycolysis promotes kidney fibrosis |
| title_full | Myeloid PFKFB3-mediated glycolysis promotes kidney fibrosis |
| title_fullStr | Myeloid PFKFB3-mediated glycolysis promotes kidney fibrosis |
| title_full_unstemmed | Myeloid PFKFB3-mediated glycolysis promotes kidney fibrosis |
| title_short | Myeloid PFKFB3-mediated glycolysis promotes kidney fibrosis |
| title_sort | myeloid pfkfb3 mediated glycolysis promotes kidney fibrosis |
| topic | macrophage glycolysis renal fibrosis PFKFB3 inflammation |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1259434/full |
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