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Kidney Week

Abstract: PO0243

Myeloid-Specific PKM2 Deletion Reduces Kidney Damage in Oxalate-Induced AKI

Session Information

  • AKI Mechanisms - 3
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Foresto-Neto, Orestes, Universidade de Sao Paulo Instituto de Ciencias Biomedicas, Sao Paulo, São Paulo, Brazil
  • Silva, Magaiver Andrade, Universidade de Sao Paulo Instituto de Ciencias Biomedicas, Sao Paulo, São Paulo, Brazil
  • Watanabe, Ingrid Kazue Mizuno, Universidade de Sao Paulo Instituto de Ciencias Biomedicas, Sao Paulo, São Paulo, Brazil
  • Honda, Tâmisa Seeko, Universidade de Sao Paulo Instituto de Ciencias Biomedicas, Sao Paulo, São Paulo, Brazil
  • Cenedeze, Marcos Antonio, Universidade Federal de Sao Paulo, Sao Paulo, São Paulo, Brazil
  • Hiyane, Meire Ioshie, Universidade de Sao Paulo Instituto de Ciencias Biomedicas, Sao Paulo, São Paulo, Brazil
  • Pacheco-Silva, Alvaro, Universidade Federal de Sao Paulo, Sao Paulo, São Paulo, Brazil
  • Camara, Niels Olsen Saraiva, Universidade de Sao Paulo Instituto de Ciencias Biomedicas, Sao Paulo, São Paulo, Brazil
Background

Reprogramming of immune cell metabolism have been associated with the development of kidney injury. The M2 isoform of pyruvate kinase (PKM2) catalyzes a critical stage of glycolysis, which was shown to be a crucial metabolic pathway for pro-inflammatory macrophages. We investigated whether deletion of PKM2 in myeloid cells exerts renoprotection in calcium oxalate (CaOx) crystal-induced acute kidney disease (AKI).

Methods

AKI was induced in myeloid-specific PKM2-knockout (PKM2fl/fl;LysM-Cre+) mice and their Cre-negative littermates (PKM2fl/fl) by a single i.p. injection of sodium oxalate (NaOx, 100mg/kg) and 3% NaOx in drinking water for 24hr before sacrifice. Healthy controls received vehicle only. Serum creatinine and urea were evaluated as markers of renal function. CaOx crystal deposition (Pizzolato staining), IL-6, NGAL and KIM-1 mRNA expression (quantitative PCR), macrophage number/phenotype (FACS), and lactate levels were assessed in kidney tissue.

Results

In PKM2fl/fl, intrarenal CaOx deposition increased the serum levels of creatinine and urea, as well as the expression of IL-6, NGAL and KIM-1 in kidney tissue compared to healthy controls (p<0.01). Despite a similar deposition of crystals, loss of renal function and markers of renal inflammation/injury were reduced in PKM2fl/fl;LysM-Cre+ (p<0.05). FACS analysis indicated that the number of F4/80+CD11b+ cells in kidneys were similarly elevated by CaOx in both PKM2fl/fl and PKM2fl/fl;LysM-Cre+, while macrophages with the pro-inflammatory phenotype Ly6C+CD206- were significantly reduced in PKM2fl/fl;LysM-Cre+ mice (p<0.01). In addition, PKM2 deletion also reduced renal levels of lactate (p<0.05).

Conclusion

The pro-inflammatory status of macrophages relays on glycolysis in CaOx nephropathy. Therefore, deletion of PKM2 in myeloid cells can reduce CaOx-induced renal inflammation and injury. FAPESP (2019/02893-9 and 2017/05264-7), CNPq and CAPES.

Funding

  • Government Support - Non-U.S.