b hydroxybutyrate attenuates renal ischemia reperfusion injury through its anti pyroptotic effects.
Ketone bodies including b hydroxybutyrate (b OHB) have been shown to protect against ischemic tissue injury when present at low concentrations. We evaluated the impact of b OHB on renal ischemia/reperfusion injury (IRI) Mice were treated with a continuous infusion of b OHB using an osmotic mini pump before and after IRI. We also tested the effects of increasing endogenous serum b OHB levels by fasting. Renal IRI was attenuated by b OHB treatment compared to saline control, with similar results in the fasting condition. b 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 b OHB treatment did not impact markers of apoptosis, it decreased the expression of caspase 1 and proinflammatory cytokines, indicating that b OHB blocked pyroptosis. In a human proximal tubular cell line exposed to hypoxia and reoxygenation, b 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 b OHB through the inactivation of histone deacetylases. In vitro, b OHB treatment restored histone acetylation at the FOXO3 promoter. Consistent with epigenetic molecular effects, the renoprotective effects of b OHB were still observed when the continuous infusion was stopped at the time of IRI. Thus, b OHB attenuates renal IRI through anti pyroptotic effects, likely mediated by an epigenetic effect on FOXO3 expression.
Kidney international