Abstract: TH-PO334

β-Hydroxybutyrate Attenuates Renal Ischemia-Reperfusion Injury

Session Information

Category: Acute Kidney Injury

  • 002 AKI: Repair and Regeneration

Authors

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


An endogenous ketone, β-hydroxybutyrate(βOHB) is used as an energy source in organs including kidney. It has been reported that βOHB 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 and human proximal cell line, HK-2 cells were used in this study. Two weeks before the study, the right kidney was removed and mice were separated into 4 groups: saline-treated sham-operated mice (n=6), βOHB-treated sham-operated mice (n=6), saline-treated mice with IR (n=8), βOHB-treated mice with IR (n=8). In IR injury mice were subject to clamping of both renal arteries and veins for 45 min and to reperfusion. βOHB 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 βOHB and molecular parameters were evaluated.

Results

In mouse study, blood urea nitrogen, serum creatinine levels, and renal tissue injury scores in βOHB-treated IR mice were significantly lower than those of saline-treated IR mice. βOHB increased histone acetylation due to the inactivation of histone deacetylase, which increased the expression of anti-oxidative factors including FOXO3, MnSOD, Catalase, Nrf2 in IR-injured kidneys and hypoxic HK-2 cells. Consistently, βOHB decreased ROS production, decreased the MDA content in IR-injured kidneys as well as in hypoxic HK-2 cells. Moreover, βOHB decreased markers of inflammasome activation including NLRP3, ASC, caspase-1, and the proinflammatory cytokines IL-1β and IL-18 expression in IR-injured kidneys as well as in hypoxic HK-2 cells. Finally, βOHB decreased Bax expression and increased Bcl-2 expression in IR-injured kidneys as well as in hypoxic HK-2 cells. Consistently, βOHB improved cell survival in hypoxic HK-2 cells and reduced the numbers of TUNEL-positive cells in IR-injured kidneys.

Conclusion


βOHB attenuates renal IR injury. The anti-oxidation, anti-inflammation and anti-apoptosis effects by βOHB, may play a role in renoprotection against renal IR injury.