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Kidney Week

Abstract: PO0151

Myeloid Lactate Dehydrogenase A (LDHA) Regulates Macrophage Polarization and Promotes Fibrosis in AKI

Session Information

  • AKI Mechanisms - 1
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Osis, Gunars, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Traylor, Amie, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Eckenrode, Hannah, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Black, Laurence Marie, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Cochrun, Steven Lee, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Agarwal, Anupam, University of Alabama at Birmingham, Birmingham, Alabama, United States
Background

Renal ischemia/reperfusion injury (IRI), a major cause of AKI, is characterized by an initial decrease of blood flow, followed by its subsequent restoration. IRI facilitates infiltration of proinflammatory macrophages as well as proliferation of intrarenal resident macrophages that, upon activation, undergo glycolytic switch, and can further exacerbate injury by inducing excessive inflammation. LDHA, a key enzyme involved in the glycolytic switch, catalyzes the conversion of pyruvate to lactate, regenerating NAD+ from NADH. Here we investigate the role of LDHA in myeloid cells and its effect on AKI.

Methods

To test the hypothesis that myeloid LDHA expression regulates macrophage polarization, RNA-Seq studies were performed in bone marrow derived macrophages (BMDM) from wild-type and LysM-Cre LDHA knockout (LDHA KO) mice grown in M-CSF for 7 days and then polarized with IFN-γ for 24 h. To test the effect of myeloid deletion on AKI, in vivo studies were performed using wild-type and LDHA KO mice using a bilateral IRI model (20 min ischemia at 37°C).

Results

RNA-seq analysis of BMDMs lacking LDHA showed significant decrease in HIF-1α and GLUT1, which are essential for the glycolytic switch. NOS2 was increased indicating diminished oxidative phosphorylation. Pro-inflammatory genes, Ccl5, IL-18, and IL-1β were downregulated. Over-representation pathway analysis (ORA) and notable altered genes are shown below (Table). While serum creatinine and GFR were similar between wild-type and LDHA KO mice, renal cortical fibrosis was significantly diminished (p<0.014) in myeloid LDHA KO mice, 7 days post IRI.

Conclusion

LDHA deficient BMDMs exhibited significant decrease in essential glycolytic switch machinery in addition to the decrease in the efficiency of oxidative phosphorylation. As a result, LDHA deficient BMDMs showed a diminished pro-inflammatory and fibrotic profile ensuing lesser renal fibrosis despite similar functional injury in both genotypes. These results suggest that LDHA is a potential target to manipulate immunometabolism in the pathogenesis of AKI.

ORA Pathways and notable genes in BMDM of LDHA KO vs WT
Pathways affected by LDHA deletionUp-regulated genesDown-regulated genes
Regulation of leukocyte activationIL-7rTnfrsf1bIL-1βIL-18
Adaptive immune responseIL-12βTnfsf4IL-27Tnfsf18
Myeloid cell differentiationItgb3Cdkn1cHif-1αIrf8
Cytokine-cytokine receptor interactionCxcl3Ccl22Ccl5Ccl6

Funding

  • NIDDK Support