{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T05:05:29Z","timestamp":1784610329250,"version":"3.55.0"},"reference-count":27,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:00:00Z","timestamp":1784246400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Boehringer Ingelheim"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cardiac arrest followed by cardiopulmonary resuscitation (CA\/CPR) induces systemic ischemia and frequently results in acute kidney injury (AKI). The ketone body \u03b2-hydroxybutyrate (BHB) maintains mitochondrial and peroxisomal homeostasis through activation of the C\/EBP\u03b2\u2013Pck1 axis, whereas Pck1 preserves mitoribosome integrity and mtDNA-encoded oxidative phosphorylation (OXPHOS) translation. However, it remains unclear whether this pathway is disrupted during CA\/CPR-induced AKI and whether empagliflozin can restore its activity. Male C57BL\/6J mice and proximal tubule-specific Pck1 conditional knockout (CKO) mice were subjected to short-duration or standard CA\/CPR protocols. Empagliflozin was administered orally for 7 days before CA\/CPR induction. Circulating BHB levels, renal expression of C\/EBP\u03b2 and Pck1, and markers of mitochondrial, peroxisomal, and mitoribosomal abundance and function were evaluated using established methods. CA\/CPR markedly reduced circulating BHB levels and suppressed the C\/EBP\u03b2\u2013Pck1 signaling axis. These changes were accompanied by depletion of peroxisomal markers, mitochondrial regulators, and mitoribosomal components as well as increased tubular apoptosis and albuminuria. Pck1 CKO mice exhibited severe organelle dysfunction and aggravated renal injury. In contrast, empagliflozin restored BHB levels, preserved C\/EBP\u03b2 and Pck1 expression, and maintained mitochondrial, peroxisomal, and mitoribosomal integrity, thereby attenuating tubular injury and albuminuria. Notably, empagliflozin treatment increased BHB, C\/EBP\u03b2, and Pck1 levels in noninjured mice without inducing organelle expansion, suggesting that Pck1 activation alone is insufficient to promote mitoribosome biogenesis under basal conditions. Collectively, these findings demonstrate that empagliflozin protects against CA\/CPR-induced AKI and identify Pck1 as a key metabolic regulator linking ketone signaling to organelle resilience.<\/jats:p>","DOI":"10.3390\/ijms27146366","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T07:54:13Z","timestamp":1784534053000},"page":"6366","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Empagliflozin Prevents Cardiac Arrest-Induced Renal Injury Through BHB-Dependent Mitoribosome Maintenance"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3113-4522","authenticated-orcid":false,"given":"Kazuhiro","family":"Hasegawa","sequence":"first","affiliation":[{"name":"Department of Nephrology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0488-0098","authenticated-orcid":false,"given":"Masanori","family":"Tamaki","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumiyo","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ikuko","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Kida","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinji","family":"Miyakami","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miho","family":"Tada","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chihiro","family":"Okinari","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Otsuka","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masanori","family":"Minato","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu","family":"Wakino","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"101934","DOI":"10.1016\/j.molmet.2024.101934","article-title":"Hepatic ketone body regulation of renal gluconeogenesis","volume":"84","author":"Hatano","year":"2024","journal-title":"Mol. Metab."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"109101","DOI":"10.1016\/j.intimp.2022.109101","article-title":"\u03b2 Hydroxybutyrate against cisplatin induced acute kidney injury via inhibiting NLRP3 inflammasome and oxidative stress","volume":"111","author":"Luo","year":"2022","journal-title":"Int. Immunopharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"149482","DOI":"10.1016\/j.bbrc.2024.149482","article-title":"Pre treatment with \u03b2 hydroxybutyrate mitigates cisplatin induced acute kidney injury","volume":"695","author":"Kim","year":"2024","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"8915","DOI":"10.1007\/s11033-023-08713-w","article-title":"\u03b2 Hydroxybutyrate ameliorates sepsis induced acute kidney injury","volume":"50","author":"Kim","year":"2023","journal-title":"Mol. Biol. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"F532","DOI":"10.1152\/ajprenal.00038.2023","article-title":"PCK1 is a key regulator of metabolic and mitochondrial functions in renal tubular cells","volume":"324","author":"Verissimo","year":"2023","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1016\/j.kint.2025.06.018","article-title":"Phosphoenolpyruvate carboxykinase 1 mediated cataplerosis is required to maintain mitochondrial fitness and to avoid kidney disease progression","volume":"108","author":"Dalga","year":"2025","journal-title":"Kidney Int."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/j.freeradbiomed.2025.01.037","article-title":"Salvianolic acid B drives gluconeogenesis and peroxisomal redox remodeling in cardiac ischemia\/reperfusion injury","volume":"229","author":"Li","year":"2025","journal-title":"Free Radic. Biol. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1681\/ASN.0000000000000156","article-title":"PCK1 protects against mitoribosomal defects in diabetic nephropathy in mouse models","volume":"34","author":"Hasegawa","year":"2023","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/s41581-023-00803-z","article-title":"New evidence of the impact of mitochondria on kidney health and disease","volume":"20","author":"Verissimo","year":"2024","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_10","first-page":"989","article-title":"Acute kidney injury after cardiac arrest: A systematic review and meta analysis of clinical studies","volume":"82","author":"Sandroni","year":"2016","journal-title":"Minerva Anestesiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1080\/21548331.2021.1931234","article-title":"Acute kidney injury and cardiac arrest in the modern era: An updated systematic review and meta analysis","volume":"49","author":"Prasitlumkum","year":"2021","journal-title":"Hosp. Pract."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e194","DOI":"10.1161\/CIR.0000000000000697","article-title":"Pediatric post\u2013cardiac arrest care: A scientific statement from the American Heart Association","volume":"140","author":"Topjian","year":"2019","journal-title":"Circulation"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"173","DOI":"10.4266\/acc.2019.00654","article-title":"Management of post cardiac arrest syndrome","volume":"34","author":"Kang","year":"2019","journal-title":"Acute Crit. Care"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.kint.2020.04.020","article-title":"Controversies in acute kidney injury: Conclusions from a KDIGO Conference","volume":"98","author":"Ostermann","year":"2020","journal-title":"Kidney Int."},{"key":"ref_15","first-page":"929","article-title":"Acute kidney injury after cardiac arrest: An unappreciated complication","volume":"82","author":"Bellomo","year":"2016","journal-title":"Minerva Anestesiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1213\/ANE.0000000000006286","article-title":"Clinical practice guidelines for the prevention of adult cardiac surgery\u2013associated acute kidney injury","volume":"136","author":"Brown","year":"2023","journal-title":"Anesth. Analg."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1186\/s13054-022-04236-1","article-title":"Higher blood pressure versus normotension targets to prevent acute kidney injury: A systematic review and meta regression","volume":"26","author":"Tran","year":"2022","journal-title":"Crit. Care"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e21098","DOI":"10.1016\/j.heliyon.2023.e21098","article-title":"\u03b2 Hydroxybutyrate as an epigenetic modifier: Underlying mechanisms and implications","volume":"9","author":"He","year":"2023","journal-title":"Heliyon"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"109915","DOI":"10.1016\/j.jnutbio.2025.109915","article-title":"Ketone bodies in renal function and diabetic kidney disease","volume":"142","author":"Mechchate","year":"2025","journal-title":"J. Nutr. Biochem."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Li, J., He, W., Wu, Q., Qin, Y., Luo, C., Dai, Z., Long, Y., Yan, P., Huang, W., and Cao, L. (2025). Ketogenic diets and \u03b2 hydroxybutyrate in diabetic kidney disease: Current progress and future perspectives. BMC Nephrol., 26.","DOI":"10.1186\/s12882-025-04019-0"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Hasegawa, K., Tamaki, M., Sakamaki, Y., and Wakino, S. (2024). Nmnat1 deficiency causes mitoribosome excess in diabetic nephropathy mediated by transcriptional repressor HIC1. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25126384"},{"key":"ref_22","first-page":"43523","article-title":"Empagliflozin attenuates global cerebral ischemic injury after cardiac arrest through enhancing ketone body oxidative metabolism in rats","volume":"15","author":"Wang","year":"2026","journal-title":"J. Am. Heart Assoc."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Annoni, F., Bogossian, E.G., Peluso, L., Su, F., Moreau, A., Nobile, L., Casu, S.G., Sterchele, E.D., Calabro, L., and Salvagno, M. (2024). Ketone bodies after cardiac arrest: A narrative review and rationale for use. Cells, 13.","DOI":"10.3390\/cells13090784"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"105602","DOI":"10.1016\/j.cryobiol.2026.105602","article-title":"Metabolic adaptations in the hypothermic myocardium: Mechanisms and clinical implications","volume":"122","author":"Wu","year":"2026","journal-title":"Cryobiology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.resuscitation.2022.01.009","article-title":"ERC\u2013ESICM guidelines on temperature control after cardiac arrest in adults","volume":"172","author":"Nolan","year":"2022","journal-title":"Resuscitation"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2039","DOI":"10.1007\/s00134-015-4051-3","article-title":"European Resuscitation Council and European Society of Intensive Care Medicine 2015 guidelines for post resuscitation care","volume":"41","author":"Nolan","year":"2015","journal-title":"Intensive Care Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/j.jjcc.2025.05.004","article-title":"SGLT2 inhibitors and cardiovascular outcomes in patients with left ventricular assist devices","volume":"86","author":"Pham","year":"2025","journal-title":"J. Cardiol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/14\/6366\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T04:23:36Z","timestamp":1784607816000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/14\/6366"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,17]]},"references-count":27,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ijms27146366"],"URL":"https:\/\/doi.org\/10.3390\/ijms27146366","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,17]]}}}