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Abstract: TH-PO745

Reduced Glycolytic ATP Production Is Responsible for Irreversible Podocyte Injury in Nephrotic Syndrome

Session Information

Category: Glomerular Diseases

  • 1403 Podocyte Biology

Authors

  • Sugimura, Masahiro, Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
  • Maeda, Kayaho, Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
  • Sato, Yuka, Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
  • Kato, Noritoshi, Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
  • Kosugi, Tomoki, Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
  • Maruyama, Shoichi, Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
Background

Energy metabolism is essential for cellular function and homeostasis, and the kidney is a high energy-consuming organ, making it susceptible to injury during aberrant energy metabolism. Podocyte energy metabolism is also critical for homeostasis under physiological condition, but its role in stress condition, especially in nephrotic syndrome involving circulatory permeability factors, is unclear. Therefore, to clarify the role of energy metabolism in injured podocytes, we examined changes in podocyte energy metabolism by circulating humoral factors of minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS).

Methods

Cultured human podocytes were treated with biopsy-proven MCD and FSGS patients’ or healthy subjects’ sera, analyzed for cell apoptosis by flow cytometry, and real-time ATP production rates in glycolysis and mitochondrial respiration using a Seahorse Extracellular Flux Analyzer. In addition, metabolomic analysis of serum-treated podocytes by GC-MS was performed to obtain an overview of energy metabolism. Isolated mouse glomeruli from Adriamycin nephropathy were also evaluated.

Results

FSGS patients’ sera significantly induced apoptosis in human podocytes compared to MCD patients’ or healthy subjects' sera. There was a correlation between decreased glycolytic ATP production and the rate of cell apoptosis in podocytes treated with FSGS patients’ sera. In addition, treatment with low concentrations of glycolytic inhibitors further induced podocyte apoptosis, despite increased mitochondrial ATP production in podocytes treated with MCD patients' sera. Metabolomic analysis also showed that glycolytic metabolites were reduced in podocytes treated with FSGS patients’ sera compared to MCD. Glycolytic enzymes were also decreased in mouse glomeruli isolated from Adriamycin nephropathy.

Conclusion

These data suggest that irreversible podocyte injury is associated with disruption of metabolic compensatory mechanisms, particularly reduced glycolytic ATP production.

Funding

  • Government Support – Non-U.S.