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Kidney Week

Abstract: PO0368

PKM2-Specific Deletion in Myeloid Cells Ameliorates Renal Impairment by Alleviating Metabolic Changes in CaOx-Induced AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Foresto-Neto, Orestes, Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil
  • Honda, Tâmisa Seeko, Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil
  • Silva, Magaiver Andrade, Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil
  • Watanabe, Ingrid Kazue Mizuno, Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil
  • Basso, Paulo Jose, Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil
  • Jesus, Iris Carvalho, Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil
  • da Silva, Ana Ruth Paolinetti Alves, Universidade Federal de Sao Paulo, Sao Paulo, São Paulo, Brazil
  • Cenedeze, Marcos A., Universidade Federal de Sao Paulo, Sao Paulo, São Paulo, Brazil
  • Hiyane, Meire Ioshie, Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil
  • Alves-Filho, José C., Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil
  • Zatz, Roberto, Universidade de Sao Paulo, 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, Sao Paulo, São Paulo, Brazil
Background

Macrophages are plastic cells and can polarize towards pro- or anti-inflammatory phenotype. PKM2 catalyzes the last step of glycolysis, which is a crucial metabolic pathway for activation of macrophages. We investigated whether deletion of PKM2 in myeloid cells would interfere with renal metabolism and exert protection in calcium oxalate (CaOx) crystal-induced acute kidney disease (AKI).

Methods

Myeloid-specific PKM2-knockout mice (PKM2fl/fl;LysM-Cre+) and their Cre-negative littermates (PKM2fl/fl) underwent AKI by a single i.p. injection of NaOx (100mg/kg) and 3% NaOx in drinking water for 24hr before sacrifice. Expression of PKM2 in bone marrow-derived macrophages was assessed by FACS. Serum creatinine, blood urea, renal CaOx crystal deposition (Pizzolato staining), IL-6, NGAL, KIM-1, HK2, CPT1a and CPT2 mRNA expression (quantitative PCR), macrophage number/phenotype (FACS), and lactate levels were all measured.

Results

In PKM2fl/fl, intrarenal CaOx deposition impaired renal function, as well as increased the expression of IL-6, NGAL, KIM-1 and HK2 and the levels of lactate in kidneys compared to healthy controls (p<0.05). Renal expression of CPT1a and CPT2 did not differ among groups. PKM2fl/fl;LysM-Cre+ exhibited similar deposition of crystals but less impairment of renal function, inflammation/injury and renal lactate content (p<0.05). The number of F4/80+CD11b+ cells in kidneys were similarly elevated by CaOx in both PKM2fl/fl and PKM2fl/fl;LysM-Cre+, while pro-inflammatory macrophages (Ly6C+CD206-) were significantly reduced in PKM2;LysM-Cre+ mice (p<0.01).

Conclusion

Pro-inflammatory macrophages rely mainly on glycolysis in oxalate induced-AKI. Deletion of PKM2 in myeloid cells partially prevents renal metabolic changes and inflammation/injury. FAPESP (2019/02893-9 and 2017/05264-7), CNPq and CAPES (Financial Code 001).

Funding

  • Government Support – Non-U.S.