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Kidney Week

Abstract: PO2444

Lactate Dehydrogenase A Influences Pro-Inflammatory Polarization of Murine Bone Marrow-Derived Macrophages

Session Information

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Osis, Gunars, The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States
  • Lu, Yan, The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States
  • Traylor, Amie, The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States
  • Zmijewska, Anna Alicja, The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States
  • Barnes, Stephen, The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States
  • Agarwal, Anupam, The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States
Background

Excessive inflammation is a major underlying pathogenic process in the progression of chronic kidney disease (CKD). Infiltration of pro-inflammatory macrophages can provoke such inflammatory responses. Macrophages undergo transcriptomic and metabolic reprogramming and rely heavily on glycolysis. Lactate Dehydrogenase A (LDHA) is a key enzyme involved in the glycolytic switch which catalyzes the conversion of pyruvate to lactate and regenerates NAD+ from NADH. Utilizing LDHA deletion, we investigated the effect of suppression of the glycolytic switch in macrophages and its effect on CKD.

Methods

Mature bone marrow-derived macrophages (BMDMs) from wild-type and LDHA knockout mice (KO) mice were cultured and then polarized for 24 hours using IFN- γ. Bulk RNA-seq (transcriptomic) and LC-MS/MS (metabolomic) experiments were performed. For in vivo studies, wild-type littermate and myeloid deficient LDHA KO were treated with aristolochic acid (AA) for 6 weeks as a model of CKD.

Results

BMDMs lacking LDHA showed a significant decrease in transcript counts of key metabolic genes involved in the glycolytic switch (HIF1a and GLUT1). LDHA deletion resulted in significantly decreased levels of aspartate indicating the arginine-succinate shunt is affected. Carnitine levels and fatty acid metabolism were significantly downregulated in the LDHA deficient macrophages. In contrast, mannose-6-phosphate levels were significantly upregulated. Combined, these changes suggest an anti-inflammatory shift. The Multi-omics approach of combining metabolomics and transcriptomic data revealed significant changes in multiple pathways including purine, nicotinate and nicotinamide metabolism. Lastly, mice lacking LDHA in myeloid cells showed a significant decrease in renal fibrosis 6 weeks post-exposure to AA in the model of CKD.

Conclusion

LDHA deficient BMDMs exhibited diminished pro-inflammatory profile in vitro and decreased renal fibrosis in vivo. These results highlight LDHA’s role as a potential target for manipulation in immunometabolism and may have a significant impact on approach to CKD.

Funding

  • NIDDK Support