Metabolomics

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Myeloid PFKFB3-mediated glycolysis promotes kidney fibrosis


ABSTRACT: 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 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 myeloid cell infiltration, as well as a decrease in the numbers of M1 and M2 macrophages and 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 phenotypes that contribute to renal fibrosis. In conclusion, our study implicates that targeting myeloid glycolysis represents a novel approach to inhibit renal fibrosis.

INSTRUMENT(S): Liquid Chromatography MS -

SUBMITTER: Qingqing Wei 

PROVIDER: MTBLS8278 | MetaboLights | 2024-03-12

REPOSITORIES: MetaboLights

Dataset's files

Source:
Action DRS
MTBLS8278 Other
FILES Other
a_MTBLS8278_LC-MS___metabolite_profiling.txt Txt
i_Investigation.txt Txt
m_MTBLS8278_LC-MS___metabolite_profiling_v2_maf.tsv Tabular
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Publications

Myeloid PFKFB3-mediated glycolysis promotes kidney fibrosis.

Yang Qiuhua Q   Huo Emily E   Cai Yongfeng Y   Zhang Zhidan Z   Dong Charles C   Asara John M JM   Shi Huidong H   Wei Qingqing Q  

Frontiers in immunology 20231116


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  ...[more]

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