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Abstract: FR-OR14

Ketone Body Metabolism in Renal Endothelium Triggers PPAR Signaling, Reduces Immune Cell Recruitment, and Preserves Kidney Function Upon Ischemia/Reperfusion Injury

Session Information

  • AKI Research: Mechanisms
    November 04, 2022 | Location: W230, Orange County Convention Center‚ West Building
    Abstract Time: 04:57 PM - 05:06 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Borri, Mila, Vlaams Instituut voor Biotechnologie KU Leuven Center for Cancer Biology, Leuven, Flemish Brabant, Belgium
  • Dumas, Sébastien J., Vlaams Instituut voor Biotechnologie KU Leuven Center for Cancer Biology, Leuven, Flemish Brabant, Belgium
  • Meta, Elda, Vlaams Instituut voor Biotechnologie KU Leuven Center for Cancer Biology, Leuven, Flemish Brabant, Belgium
  • Bouché, Ann, Vlaams Instituut voor Biotechnologie KU Leuven Center for Cancer Biology, Leuven, Flemish Brabant, Belgium
  • Saraber, Pepijn, Vlaams Instituut voor Biotechnologie KU Leuven Center for Cancer Biology, Leuven, Flemish Brabant, Belgium
  • García-Caballero, Melissa, Vlaams Instituut voor Biotechnologie KU Leuven Center for Cancer Biology, Leuven, Flemish Brabant, Belgium
  • Veiga, Nuphar, Vlaams Instituut voor Biotechnologie KU Leuven Center for Cancer Biology, Leuven, Flemish Brabant, Belgium
  • Kalucka, Joanna, Vlaams Instituut voor Biotechnologie KU Leuven Center for Cancer Biology, Leuven, Flemish Brabant, Belgium
  • Eelen, Guy, Vlaams Instituut voor Biotechnologie KU Leuven Center for Cancer Biology, Leuven, Flemish Brabant, Belgium
  • Carmeliet, Peter, Vlaams Instituut voor Biotechnologie KU Leuven Center for Cancer Biology, Leuven, Flemish Brabant, Belgium
Background

Renal ischemia/reperfusion injury (IRI), a major cause of acute kidney injury (AKI), affects cellular energy state, induces oxidative stress and immune cell recruitment, ultimately impairing kidney function. Targeting renal endothelial cells (ECs) could prevent kidney dysfunction and improve the outcome for patients with IRI-related AKI. Ketone body supplementation protects against IRI. Renal ECs are directly exposed to circulating ketone bodies but their contribution to the protective effect and possible underlying mechanisms remain unknown.

Methods

Oxct1WT and Oxct1ΔECKO mice (lacking the rate-limiting enzyme of ketolysis in ECs) were fed a chow or ketogenic diet (KD) and exposed to sham surgery or bilateral clamping of renal pedicles. Kidney function (plasma markers) and injury (histology) were assessed 24h after reperfusion. Renal ECs were freshly isolated and submitted to bulk RNA-seq. Immune cell populations in kidneys were analyzed by flow cytometry. Gene expression was assessed in OXCT1-silenced HUVECs by qPCR.

Results

KD improved kidney function, decreased tubule injury and immune cell infiltration in kidneys of mice exposed to renal IRI. These effects were partly impaired in Oxct1ΔECKO mice, highlighting the role of EC ketolysis. Transcriptomics analysis of renal ECs upon IRI showed upregulation of immune activation genes and downregulation of metabolic genes involved in fatty acid, arachidonic acid, and glutathione metabolism, among others. KD partially reverted this gene signature in Oxct1WT ECs, but only to a limited extent in Oxct1KO ECs. Geneset enrichment analysis identified PPAR signaling as a potential hub downstream of ketolysis, since oppositely regulated by KD and Oxct1 knockout. OXCT1-silenced HUVECs upregulated immune activation genes, suggesting an anti-inflammatory role of ketolysis in ECs.

Conclusion

EC ketolysis partly mediated the KD protective effect in a mouse model of renal IRI, by preventing renal EC activation, reducing immune cell recruitment, maintaining a metabolic homeostasis in ECs, and preventing kidney function impairment. Activation of the metabolic regulator PPAR in ECs appears to contribute to this protective mechanism in IRI.

Funding

  • Government Support – Non-U.S.