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Kidney Week

Abstract: SA-PO568

β-Hydroxybutyrate Attenuates Renal Ischemia-Reperfusion Injury Through Its Anti-Pyroptotic Effects via Epigenetic Mechanism

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Tajima, Takaya, Keio medical university, TOKYO, Japan
  • Matsui, Ayumi, Keio medical university, TOKYO, Japan
  • Ito, Tomoaki, Keio medical university, TOKYO, Japan
  • Uchiyama, Kiyotaka, Keio University, School of Medicine, Tokyo, Japan
  • Wakino, Shu, Keio University, Tokyo-to, Japan
  • Itoh, Hiroshi, Keio University School of Medicine, Tokyo, Japan
Background


An endogenous ketone, β-hydroxybutyrate(β-OHB) is used as an energy source in various organs including kidney and has therapeutic benefits against stress conditions. In this study, we evaluated its protective effects and potential mechanisms in renal ischemia/reperfusion injury(IR).

Methods

Male C57BL/6J mice undetook heminephrectomy and separated into 4 groups: saline-treated sham-operated mice (Sham: n=6), β-OHB-treated sham mice (Sham+β-OHB ; n=6), saline-treated mice with IR (IR; n=8), β-OHB-treated mice with IR (IR+β-OHB; n=8). In IR injury mice were subject to clamping of both renal arteries and veins for 45 min and to reperfusion. β-OHB was administered continuously by osmotic mini-pump at the dose of 8 mg/h. Kidneys were harvested 24 h after IR injury, and functional and molecular parameters were evaluated. In vitro studies, HK-2 cells were incubated for 1 h with mineral oil to induce hypoxic injury, and incubated for 24 h after medium replacement. These HK-2 cells were treated with various doses of β-OHB and molecular parameters were evaluated.

Results


In IR mice, blood urea nitrogen, serum creatinine levels, and renal tissue injury scores were significantly higher than those in control mice. These values were significantly lowered in IR+β-OHB group. β-OHB treatment significantly reduced the TUNEL-positive cell number and increased FOXO3 and its downstream target molecule, apoptosis repressor with caspase recruitment domain (ARC) expressions. Although β-OHB unchanged the apoptotic markers, it decreased the expressions of caspase-1, the proinflammatory cytokines interleukin (IL)-1β and IL-18 in IR-injured kidneys, indicating that β-OHB blocked pyroptotic cell death rather than apoptotic cell death. In HK-2 cell subject to hypoxic insult, β-OHB reduced the number of cell death through the inhibition of pyroptosis pathway in FOXO3-dependent fashion. Histone acetylation deceased in IR mice and in hypoxic HK-2 cells through the inactivation of histone acetyltransferase activity. This reduction was ameliorated by β-OHB through the inactivation of histone deacetylase.

Conclusion


β-OHB attenuates renal IR injury by its anti-pyroptotic effect through its epigenetic effects on FOXO3 expression.