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Identify the changed genes that are regulated by Ppp2ca [RNA-seq]

ABSTRACT: Ppp2ca is a subunit of PP2A complex, which plays critical roles in variaty of tumors and autoimmune diseases. Deletion of Ppp2ca in mice led to hematopoietic disorders, showing increased myeloid differentiation and decreased lymphoid differentiation. Metabolic analysis indicated that Ppp2ca deficiency resulted in aerobic glycolysis in hematopoietic stem cells (HSCs), with elevated levels of lactate. Genetic deletion of LDHA or blocking of lactate metabolism was found to be able to rescue the phenotypic abnormal caused by Ppp2ca insufficiency. Therefore, this study proposed that LDHA could be served as a novel target for the treatment of Ppp2ca related diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE248148 | GEO | 2025/11/11

REPOSITORIES: GEO

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Project description:Background: In acute kidney injury, macrophages play a major role in regulating inflammation. Classically activated macrophages (M1) undergo drastic metabolic reprogramming during their differentiation and upregulate the aerobic glycolysis pathway to fulfill their pro-inflammatory functions. NAD+ regeneration is crucial for the maintenance of glycolysis and the most direct pathway by which this occurs is via the fermentation of pyruvate to lactate, catalyzed by lactate dehydrogenase A (LDHA). Our previous study determined that LDHA is predominantly expressed in the proximal segments of the nephron in the mouse kidney and increases with hypoxia. This study investigates the potential of LDHA as a therapeutic target for inflammation by exploring its role in macrophage function in vitro. Methods: Bone-marrow-derived macrophages (BMDMs) were isolated from myeloid-specific LDHA knockout mice derived from crossbreeding LysM-Cre transgenic mice and LDHA floxed mice. RNA sequencing and LC-MS/MS metabolomics analyses were used in this study to determine the effect of LDHA deletion on BMDM following stimulation with IFN-γ. Results: LDHA deletion in IFN-γ BMDMs resulted in a significant alteration of the macrophage activation and functional pathways, and change in glycolytic, cytokine, and chemokine gene expression. Metabolite concentrations associated with pro-inflammatory macrophage profiles were diminished while anti-inflammatory-associated ones were increased in LDHA KO BMDMs. Glutamate and amino sugars metabolic pathways were significantly affected by the LDHA deletion. A combined muti-omics analysis highlighted changes in Rap1 signaling, cytokine-cytokine receptor interaction, focal adhesion, and MAPK signaling metabolism pathways. Conclusions: Deletion of LDHA in macrophages results in a notable reduction in the pro-inflammatory profile and concurrent upregulation of anti-inflammatory pathways. These findings suggest that LDHA could serve as a promising therapeutic target for inflammation, a key contributor to the pathogenesis of acute kidney injury.

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Identify the changed genes that are regulated by Ppp2ca [RNA-seq]

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