Kidney Week

Abstract: PO0368

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

Session Information

• AKI: Mechanisms of Injury
  November 04, 2021 | Location: On-Demand, Virtual Only
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Foresto-Neto, Orestes, Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil

Orestes Foresto-Neto, PhD

• Honda, Tâmisa Seeko, Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil

Tâmisa Seeko Honda,

• Silva, Magaiver Andrade, Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil

Magaiver Andrade Silva,

• Watanabe, Ingrid Kazue Mizuno, Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil

Ingrid Kazue Mizuno Watanabe,

• Basso, Paulo Jose, Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil

Paulo Jose Basso,

• Jesus, Iris Carvalho, Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil

Iris Carvalho Jesus,

• da Silva, Ana Ruth Paolinetti Alves, Universidade Federal de Sao Paulo, Sao Paulo, São Paulo, Brazil

Ana Ruth Paolinetti Alves da Silva,

• Cenedeze, Marcos A., Universidade Federal de Sao Paulo, Sao Paulo, São Paulo, Brazil

Marcos A. Cenedeze,

• Hiyane, Meire Ioshie, Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil

Meire Ioshie Hiyane,

• Alves-Filho, José C., Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil

José C. Alves-Filho,

• Zatz, Roberto, Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil

Roberto Zatz,

• Pacheco-Silva, Alvaro, Universidade Federal de Sao Paulo, Sao Paulo, São Paulo, Brazil

Alvaro Pacheco-Silva,

• Camara, Niels Olsen Saraiva, Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil

Niels Olsen Saraiva Camara,

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 (PKM2^fl/fl;LysM-Cre⁺) and their Cre-negative littermates (PKM2^fl/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 PKM2^fl/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. PKM2^fl/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 PKM2^fl/fl and PKM2^fl/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.