β-hydroxybutyrate attenuates renal ischemia-reperfusion injury through its anti-pyroptotic effects

Takaya Tajima, Ayumi Yoshifuji, Ayumi Matsui, Tomoaki Itoh, Kiyotaka Uchiyama, Takeshi Kanda, Hirobumi Tokuyama, Shu Wakino, Hiroshi Itoh

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Ketone bodies including β-hydroxybutyrate (β-OHB) have been shown to protect against ischemic tissue injury when present at low concentrations. We evaluated the impact of β-OHB on renal ischemia/reperfusion injury (IRI). Mice were treated with a continuous infusion of β-OHB using an osmotic mini-pump before and after IRI. We also tested the effects of increasing endogenous serum β-OHB levels by fasting. Renal IRI was attenuated by β-OHB treatment compared to saline control, with similar results in the fasting condition. β-OHB treatment reduced the number of terminal deoxynucleotidyl transferase–mediated dUTP nick end-labeling (TUNEL)-positive cells and increased expression of forkhead transcription factor O3 (FOXO3), an upstream regulator of pyroptosis. Although β-OHB treatment did not impact markers of apoptosis, it decreased the expression of caspase-1 and proinflammatory cytokines, indicating that β-OHB blocked pyroptosis. In a human proximal tubular cell line exposed to hypoxia and reoxygenation, β-OHB reduced cell death in a FOXO3-dependent fashion. Histone acetylation was decreased in kidneys exposed to IRI and in proximal tubular cells exposed to hypoxia and reoxygenation, and this effect was ameliorated by β-OHB through the inactivation of histone deacetylases. In vitro, β-OHB treatment restored histone acetylation at the FOXO3 promoter. Consistent with epigenetic molecular effects, the renoprotective effects of β-OHB were still observed when the continuous infusion was stopped at the time of IRI. Thus, β-OHB attenuates renal IRI through anti-pyroptotic effects, likely mediated by an epigenetic effect on FOXO3 expression.

Original languageEnglish
Pages (from-to)1120-1137
Number of pages18
JournalKidney international
Volume95
Issue number5
DOIs
Publication statusPublished - 2019 May

Keywords

  • acute kidney injury
  • cell death
  • cell survival
  • inflammation
  • ischemia reperfusion

ASJC Scopus subject areas

  • Nephrology

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