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

Abstract

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.

Tisp40 Induces Tubular Epithelial Cell GSDMD-Mediated Pyroptosis in Renal Ischemia-Reperfusion Injury via NF-κB Signaling

“…It forms pores in the plasma membrane that ultimately cause cell swelling, membrane lysis, and inflammatory cytokines release (Shi et al, 2015). GSDMD-mediated pyroptosis of renal TECs is an essential process in renal ischemia-reperfusion (I/R) injury (Diao et al, 2019;Tajima et al, 2019;Liu et al, 2020). Thus, studies are needed to determine the biological networks involved in GSDMD-mediated pyroptosis in TEC injury induced by renal IR.…”

7-Hydroxycoumarin Attenuates Colistin-Induced Kidney Injury in Mice Through the Decreased Level of Histone Deacetylase 1 and the Activation of Nrf2 Signaling Pathway

“…Increasing evidences have emphasized the importance of HDAC-regulated epigenetic modification in the development of kidney injury (Wang et al, 2014;Ma et al, 2017;Yoshikazu et al, 2018). When exposed to ischemia/reperfusion injury, histone acetylation modification of kidneys was reduced, while b-hydroxybutyrate attenuates kidney injury by restoring histone acetylation at the FOXO3 promoter (Takaya et al, 2019). In addition, targeting histone H4 acetylation via phosphoinositide 3-kinase-and p70s6-kinasedependent pathways could inhibit iNOS production and alleviated injury in glomerular mesangial cells (Yu and Kone, 2006).…”

FOXO1 inhibition prevents renal ischemia–reperfusion injury via cAMP‐response element binding protein/PPAR‐γ coactivator‐1α‐mediated mitochondrial biogenesis

“…Moreover, the t 1/2 of FOXO1 was decreased ( Figure S2A) and protein level of FOXO1 was up-regulated in HK2s exposed to H/ R. The elevated protein levels were due to enhanced transcription of FOXO1. It has been reported that the protein expression of FOXO3 was attenuated in I/R renal tissue and or H/R HK2 cells (Tajima et al, 2019;Wu et al, 2016). Moreover, we only focused on FOXO1 function in renal I/R injury because AS1842856 is a selective inhibitor that blocks the transcription activity of FOXO1 (IC 50 : 33 nM;Nagashima et al, 2010).…”