480-P: Reversal of Diabetic Nephropathy in T2D db/db Mouse Model by Systemic Pyruvate Kinase M2 (PKM2) Activation

Background: The development of thoracic aortic aneurysm and dissection (TAAD) is mediated by inflammasome activation, which exacerbates the secretion of pro-inflammatory cytokines, chemokines, matrix metalloproteinases (MMPs), and reactive oxygen species (ROS). The glycolytic enzyme pyruvate kinase M2 (PKM2) has shown a protective role against various disorders with an inflammatory basis, such as sepsis, tumorigenesis, and diabetic nephropathy. However, its potential role in TAAD has not been investigated so far. Approach and Results: We analyzed aortic tissues from TAAD patients and the β-aminopropionitrile fumarate (BAPN)–induced mouse model of TAAD and observed elevated levels of PKM2 in the aortic lesions of both. Treatment with the PKM2 activator TEPP-46 markedly attenuated the progression of TAAD in the mouse model as demonstrated by decreased morbidity and luminal diameter of the aorta. In addition, the thoracic aortas of the BAPN-induced mice showed reduced monocytes and macrophages infiltration and lower levels of IL-1β, MMPs, and ROS when treated with TEPP-46. Furthermore, TEPP-46 treatment also suppressed the activation of the NOD-like receptor (NLR) family and pyrin domain–containing protein 3 (NLRP3) inflammasome by downregulating p-STAT3 and HIF1-α. Conclusion: Pyruvate kinase M2 plays a protective role in TAAD development, and its activation is a promising therapeutic strategy against the progression of TAAD.

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Dysregulation of Pyruvate Kinase M2 Promotes Inflammation in a Mouse Model of Obese Allergic Asthma

American Journal of Respiratory Cell and Molecular Biology ◽

10.1165/rcmb.2020-0512oc ◽

2021 ◽

Author(s):

Allison M. Manuel ◽

Cheryl van de Wetering ◽

Maximilian MacPherson ◽

Cuixia Erickson ◽

Caliann Murray ◽

...

Keyword(s):

Mouse Model ◽

Allergic Asthma ◽

Pyruvate Kinase ◽

Pyruvate Kinase M2

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The Effect of Pyruvate Kinase M2: Inhibitor(shikonin) on the Function of Mdc in Severe Aplastic Anemia Mouse Model

Blood ◽

10.1182/blood-2019-126726 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5021-5021

Author(s):

Mengying Zheng ◽

Chunyan Liu ◽

Yuanyuan Shao ◽

Rong Fu ◽

Huaquan Wang ◽

...

Keyword(s):

Mouse Model ◽

Aplastic Anemia ◽

Pyruvate Kinase ◽

Conflicts Of Interest ◽

Bone Marrow Failure ◽

Autoimmune Response ◽

Severe Aplastic Anemia ◽

Pyruvate Kinase M2 ◽

Cd8 Cells ◽

Cytotoxic Molecules

Severe aplastic anemia (SAA) is a rare disease characterized by severe pancytopenia and bone marrow failure. Over-activated myeloid dendritic cells (mDCs) play an important role in the pathogenesis of SAA. In recent years, the role of pyruvate kinase M2 (PKM2) in DC function and autoimmune response has been gradually recognized. In this study, an immune attack-mediated AA mouse model was constructed by total body irradiation and lymphocyte infusion. The AA model mice showed pancytopenia, decreased ratio of CD4+/CD8+ cells, increased expression of cytotoxic molecules perforin and granzyme in CD8+ cells, increased levels of co-stimulatory molecules CD80 and CD86 in DCs and inadequate Treg number. In-vitro animal experiments confirmed the activation of PKM2 in mDCs, which promoted glycolytic metabolism. High levels of PKM2 in mice contributed to the poor survival rate. Additionally, intervention treatment with shikonin or cyclosporin A in the AA mouse model reduced the expression not only of co-stimulatory molecules CD80 and CD86 in mDCs but also of cytotoxic molecules in CD8+ cells. In conclusion, we confirmed the activation of PKM2 in mDCs in AA mouse models. PKM2 is involved in mDC activation and proliferation, which might contribute to activating the downstream cytotoxic T cells (CTLs). PKM2 is a possible novel target in SAA treatment. Disclosures No relevant conflicts of interest to declare.

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