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β-hydroxybutyrate ameliorates sepsis-induced acute kidney injury

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Abstract

Background

Sepsis is a major cause of acute kidney injury (AKI). Recent studies have demonstrated that β-hydroxybutyrate (β-HB) alleviates renal ischemia-reperfusion injury and cisplatin-induced renal injury in murine models. This study aimed to investigate whether β-HB ameliorates sepsis-induced AKI (SIAKI) in a lipopolysaccharide (LPS)-induced mouse sepsis model.

Methods and results

SIAKI was induced by intraperitoneally injecting LPS to C57BL/6 male mice. β-HB was administrated intraperitoneally before LPS injection. The mice were divided into sham, β-HB, LPS, and β-HB + LPS groups. The histological damage score and serum creatinine level were significantly increased in the LPS group mice, but attenuated in the β-HB + LPS group mice. The expression of phosphorylated nuclear factor-κB tumor necrosis factor-α/interleukin-6 and the number of F4/80-positive macrophages in the β-HB + LPS group mice were lower than those in the LPS group mice. The number of TdT-mediated dUTP nick-end labeling (TUNEL)-positive tubular cells, cleaved caspase-3 expression, and Bax/Bcl-2 ratio in the β-HB + LPS group mice were lower than those in the LPS group mice.

Conclusion

β-HB pre-treatment ameliorates SIAKI by reducing tubular apoptosis and inflammatory responses. Thus, β-HB pre-treatment could be a potential prophylactic strategy against SIAKI.

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Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Case J, Khan S, Khalid R, Khan A (2013) Epidemiology of acute kidney injury in the intensive care unit. Crit Care Res Pract 2013:479730. https://doi.org/10.1155/2013/479730

    Article  PubMed  PubMed Central  Google Scholar 

  2. Susantitaphong P, Cruz DN, Cerda J, Abulfaraj M, Alqahtani F, Koulouridis I, Jaber BL, Acute Kidney Injury Advisory Group of the American Society of N (2013) World incidence of AKI: a meta-analysis. Clin J Am Soc Nephrol 8:1482–1493. https://doi.org/10.2215/CJN.00710113

    Article  PubMed  PubMed Central  Google Scholar 

  3. Hoste EA, Bagshaw SM, Bellomo R, Cely CM, Colman R, Cruz DN, Edipidis K, Forni LG, Gomersall CD, Govil D, Honore PM, Joannes-Boyau O, Joannidis M, Korhonen AM, Lavrentieva A, Mehta RL, Palevsky P, Roessler E, Ronco C, Uchino S, Vazquez JA, Vidal Andrade E, Webb S, Kellum JA (2015) Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med 41:1411–1423. https://doi.org/10.1007/s00134-015-3934-7

    Article  PubMed  Google Scholar 

  4. Bagshaw SM, Uchino S, Bellomo R, Morimatsu H, Morgera S, Schetz M, Tan I, Bouman C, Macedo E, Gibney N, Tolwani A, Oudemans-van Straaten HM, Ronco C, Kellum JA, Beginning, Ending Supportive Therapy for the Kidney I (2007) Septic acute kidney injury in critically ill patients: clinical characteristics and outcomes. Clin J Am Soc Nephrol 2:431–439. https://doi.org/10.2215/CJN.03681106

    Article  PubMed  Google Scholar 

  5. Puchalska P, Crawford PA (2021) Metabolic and signaling roles of Ketone Bodies in Health and Disease. Annu Rev Nutr 41:49–77. https://doi.org/10.1146/annurev-nutr-111120-111518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Wells J, Swaminathan A, Paseka J, Hanson C (2020) Efficacy and safety of a ketogenic Diet in Children and Adolescents with Refractory Epilepsy-A Review. Nutrients 12. https://doi.org/10.3390/nu12061809

  7. Miyauchi T, Uchida Y, Kadono K, Hirao H, Kawasoe J, Watanabe T, Ueda S, Okajima H, Terajima H, Uemoto S (2019) Up-regulation of FOXO1 and reduced inflammation by beta-hydroxybutyric acid are essential diet restriction benefits against liver injury. Proc Natl Acad Sci U S A 116:13533–13542. https://doi.org/10.1073/pnas.1820282116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Snorek M, Hodyc D, Sedivy V, Durisova J, Skoumalova A, Wilhelm J, Neckar J, Kolar F, Herget J (2012) Short-term fasting reduces the extent of myocardial infarction and incidence of reperfusion arrhythmias in rats. Physiol Res 61:567–574. https://doi.org/10.33549/physiolres.932338

    Article  CAS  PubMed  Google Scholar 

  9. Zou Z, Sasaguri S, Rajesh KG, Suzuki R (2002) Dl-3-Hydroxybutyrate administration prevents myocardial damage after coronary occlusion in rat hearts. Am J Physiol Heart Circ Physiol 283. https://doi.org/10.1152/ajpheart.00250.2002. :H1968-1974

  10. Edwards C, Copes N, Bradshaw PC (2015) D-ss-hydroxybutyrate: an anti-aging ketone body. Oncotarget 6:3477–3478. https://doi.org/10.18632/oncotarget.3423

    Article  PubMed  PubMed Central  Google Scholar 

  11. Kim DH, Park MH, Ha S, Bang EJ, Lee Y, Lee AK, Lee J, Yu BP, Chung HY (2019) Anti-inflammatory action of beta-hydroxybutyrate via modulation of PGC-1alpha and FoxO1, mimicking calorie restriction. Aging 11:1283–1304. https://doi.org/10.18632/aging.101838

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Stekovic S, Hofer SJ, Tripolt N, Aon MA, Royer P, Pein L, Stadler JT, Pendl T, Prietl B, Url J, Schroeder S, Tadic J, Eisenberg T, Magnes C, Stumpe M, Zuegner E, Bordag N, Riedl R, Schmidt A, Kolesnik E, Verheyen N, Springer A, Madl T, Sinner F, de Cabo R, Kroemer G, Obermayer-Pietsch B, Dengjel J, Sourij H, Pieber TR, Madeo F (2019) Alternate day fasting improves physiological and molecular markers of aging in Healthy, non-obese humans. Cell Metab 30:462–476e466. https://doi.org/10.1016/j.cmet.2019.07.016

    Article  CAS  PubMed  Google Scholar 

  13. Mikami D, Kobayashi M, Uwada J, Yazawa T, Kamiyama K, Nishimori K, Nishikawa Y, Morikawa Y, Yokoi S, Takahashi N, Kasuno K, Taniguchi T, Iwano M (2019) beta-hydroxybutyrate, a ketone body, reduces the cytotoxic effect of cisplatin via activation of HDAC5 in human renal cortical epithelial cells. Life Sci 222:125–132. https://doi.org/10.1016/j.lfs.2019.03.008

    Article  CAS  PubMed  Google Scholar 

  14. Tajima T, Yoshifuji A, Matsui A, Itoh T, Uchiyama K, Kanda T, Tokuyama H, Wakino S, Itoh H (2019) beta-hydroxybutyrate attenuates renal ischemia-reperfusion injury through its anti-pyroptotic effects. Kidney Int 95:1120–1137. https://doi.org/10.1016/j.kint.2018.11.034

    Article  CAS  PubMed  Google Scholar 

  15. Wei T, Tian W, Liu F, Xie G (2014) Protective effects of exogenous beta-hydroxybutyrate on paraquat toxicity in rat kidney. Biochem Biophys Res Commun 447:666–671. https://doi.org/10.1016/j.bbrc.2014.04.074

    Article  CAS  PubMed  Google Scholar 

  16. Torres JA, Kruger SL, Broderick C, Amarlkhagva T, Agrawal S, Dodam JR, Mrug M, Lyons LA, Weimbs T (2019) Ketosis ameliorates renal cyst growth in polycystic kidney disease. Cell Metab 30:1007–1023e1005. https://doi.org/10.1016/j.cmet.2019.09.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Qi H, Gu L, Xu D, Liu K, Zhou M, Wang Y, Wang X, Li Y, Qi J (2021) beta-hydroxybutyrate inhibits cardiac microvascular collagen 4 accumulation by attenuating oxidative stress in streptozotocin-induced diabetic rats and high glucose treated cells. Eur J Pharmacol 899:174012. https://doi.org/10.1016/j.ejphar.2021.174012

    Article  CAS  PubMed  Google Scholar 

  18. Tomita I, Kume S, Sugahara S, Osawa N, Yamahara K, Yasuda-Yamahara M, Takeda N, Chin-Kanasaki M, Kaneko T, Mayoux E, Mark M, Yanagita M, Ogita H, Araki SI, Maegawa H (2020) SGLT2 inhibition mediates Protection from Diabetic kidney disease by promoting Ketone Body-Induced mTORC1 inhibition. Cell Metab 32:404–419e406. https://doi.org/10.1016/j.cmet.2020.06.020

    Article  CAS  PubMed  Google Scholar 

  19. Fang Y, Chen B, Gong AY, Malhotra DK, Gupta R, Dworkin LD, Gong R (2021) The ketone body beta-hydroxybutyrate mitigates the senescence response of glomerular podocytes to diabetic insults. Kidney Int 100:1037–1053. https://doi.org/10.1016/j.kint.2021.06.031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kim IY, Song SH, Seong EY, Lee DW, Bae SS, Lee SB (2023) Akt1 is involved in renal fibrosis and tubular apoptosis in a murine model of acute kidney injury-to-chronic kidney disease transition. Exp Cell Res 424:113509. https://doi.org/10.1016/j.yexcr.2023.113509

    Article  CAS  PubMed  Google Scholar 

  21. Wu L, Gokden N, Mayeux PR (2007) Evidence for the role of reactive nitrogen species in polymicrobial sepsis-induced renal peritubular capillary dysfunction and tubular injury. J Am Soc Nephrol 18:1807–1815. https://doi.org/10.1681/ASN.2006121402

    Article  CAS  PubMed  Google Scholar 

  22. Peerapornratana S, Manrique-Caballero CL, Gomez H, Kellum JA (2019) Acute kidney injury from sepsis: current concepts, epidemiology, pathophysiology, prevention and treatment. Kidney Int 96:1083–1099. https://doi.org/10.1016/j.kint.2019.05.026

    Article  PubMed  PubMed Central  Google Scholar 

  23. Liu SF, Malik AB (2006) NF-kappa B activation as a pathological mechanism of septic shock and inflammation. Am J Physiol Lung Cell Mol Physiol 290:L622–L645. https://doi.org/10.1152/ajplung.00477.2005

    Article  CAS  PubMed  Google Scholar 

  24. Havasi A, Borkan SC (2011) Apoptosis and acute kidney injury. Kidney Int 80:29–40. https://doi.org/10.1038/ki.2011.120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Han SJ, Lee HT (2019) Mechanisms and therapeutic targets of ischemic acute kidney injury. Kidney Res Clin Pract 38:427–440. https://doi.org/10.23876/j.krcp.19.062

    Article  PubMed  PubMed Central  Google Scholar 

  26. Virzi GM, Mattiotti M, de Cal M, Ronco C, Zanella M, De Rosa S (2022) Endotoxin in Sepsis: methods for LPS detection and the Use of Omics techniques. Diagnostics (Basel) 13. https://doi.org/10.3390/diagnostics13010079

  27. He FF, Wang YM, Chen YY, Huang W, Li ZQ, Zhang C (2022) Sepsis-induced AKI: from pathogenesis to therapeutic approaches. Front Pharmacol 13:981578. https://doi.org/10.3389/fphar.2022.981578

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Mierziak J, Burgberger M, Wojtasik W (2021) 3-Hydroxybutyrate as a metabolite and a Signal Molecule regulating processes of living organisms. Biomolecules 11. https://doi.org/10.3390/biom11030402

  29. Yang Q, Liu R, Yu Q, Bi Y, Liu G (2019) Metabolic regulation of inflammasomes in inflammation. Immunology 157:95–109. https://doi.org/10.1111/imm.13056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Chang MY, Chang SY, Su PP, Tian F, Liu ZS (2021) The protective effect of beta-hydroxybutyric acid on renal glomerular epithelial cells in adriamycin-induced injury. Am J Transl Res 13:8847–8859

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Garofalo AM, Lorente-Ros M, Goncalvez G, Carriedo D, Ballen-Barragan A, Villar-Fernandez A, Penuelas O, Herrero R, Granados-Carreno R, Lorente JA (2019) Histopathological changes of organ dysfunction in sepsis. Intensive Care Med Exp 7:45. https://doi.org/10.1186/s40635-019-0236-3

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2021R1F1A1059497).

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Authors and Affiliations

  1. Department of Internal Medicine, Pusan National University School of Medicine, Yangsan, Republic of Korea

    Min Jeong Kim, Seo Rin Kim, Dong Won Lee, Soo Bong Lee & Il Young Kim

  2. Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea

    Min Jeong Kim, Young Suk Kim, Seo Rin Kim, Dong Won Lee, Soo Bong Lee & Il Young Kim

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Contributions

MJK, IYK, and SBL designed the study. MJK, IYK, and YSK performed experiments. MJK, SRK, YSK, DWL, SBL and IYK analyzed and interpreted data. MJK and IYK wrote the manuscript. SRK, DWL, and SSB supervised the study. All authors approved the final manuscript.

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Correspondence to Il Young Kim.

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The authors declare no conflicts of interest.

Ethics approval.

Study animal protocols (PNU, 2021-037) were reviewed and approved by Pusan National University–Institutional Animal Care and Use Committee (PNU-IACUC) with respect to ethics and husbandry.

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Kim, M.J., Kim, Y.S., Kim, S.R. et al. β-hydroxybutyrate ameliorates sepsis-induced acute kidney injury. Mol Biol Rep 50, 8915–8923 (2023). https://doi.org/10.1007/s11033-023-08713-w

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