{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:20:10Z","timestamp":1790742010440,"version":"4.1.0"},"reference-count":79,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2022,9,3]],"date-time":"2022-09-03T00:00:00Z","timestamp":1662163200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008530","name":"the European Union through the European Regional Development Fund","doi-asserted-by":"publisher","award":["2014-2020.4.01.15-0012"],"award-info":[{"award-number":["2014-2020.4.01.15-0012"]}],"id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008530","name":"the European Union through the European Regional Development Fund","doi-asserted-by":"publisher","award":["EEZ\/BPP\/VIAA\/2021\/8"],"award-info":[{"award-number":["EEZ\/BPP\/VIAA\/2021\/8"]}],"id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008530","name":"the European Union through the European Regional Development Fund","doi-asserted-by":"publisher","award":["PUT1077"],"award-info":[{"award-number":["PUT1077"]}],"id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008530","name":"the European Union through the European Regional Development Fund","doi-asserted-by":"publisher","award":["PRG685"],"award-info":[{"award-number":["PRG685"]}],"id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Baltic Research Programme of the European Economic Area (EEA)","award":["2014-2020.4.01.15-0012"],"award-info":[{"award-number":["2014-2020.4.01.15-0012"]}]},{"name":"Baltic Research Programme of the European Economic Area (EEA)","award":["EEZ\/BPP\/VIAA\/2021\/8"],"award-info":[{"award-number":["EEZ\/BPP\/VIAA\/2021\/8"]}]},{"name":"Baltic Research Programme of the European Economic Area (EEA)","award":["PUT1077"],"award-info":[{"award-number":["PUT1077"]}]},{"name":"Baltic Research Programme of the European Economic Area (EEA)","award":["PRG685"],"award-info":[{"award-number":["PRG685"]}]},{"DOI":"10.13039\/501100002301","name":"Estonian Research Foundation","doi-asserted-by":"publisher","award":["2014-2020.4.01.15-0012"],"award-info":[{"award-number":["2014-2020.4.01.15-0012"]}],"id":[{"id":"10.13039\/501100002301","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002301","name":"Estonian Research Foundation","doi-asserted-by":"publisher","award":["EEZ\/BPP\/VIAA\/2021\/8"],"award-info":[{"award-number":["EEZ\/BPP\/VIAA\/2021\/8"]}],"id":[{"id":"10.13039\/501100002301","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002301","name":"Estonian Research Foundation","doi-asserted-by":"publisher","award":["PUT1077"],"award-info":[{"award-number":["PUT1077"]}],"id":[{"id":"10.13039\/501100002301","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002301","name":"Estonian Research Foundation","doi-asserted-by":"publisher","award":["PRG685"],"award-info":[{"award-number":["PRG685"]}],"id":[{"id":"10.13039\/501100002301","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Ischemia reperfusion injury is common in transplantation. Previous studies have shown that cooling can protect against hypoxic injury. To date, the protective effects of hypothermia have been largely associated with metabolic suppression. Since kidney transplantation is one of the most common organ transplant surgeries, we used human-derived renal proximal tubular cells (HKC8 cell line) as a model of normal renal cells. We performed a temperature titration curve from 37 \u00b0C to 22 \u00b0C and evaluated cellular respiration and molecular mechanisms that can counteract the build-up of reducing equivalents in hypoxic conditions. We show that the protective effects of hypothermia are likely to stem both from metabolic suppression (inhibitory component) and augmentation of stress tolerance (activating component), with the highest overlap between activating and suppressing mechanisms emerging in the window of mild hypothermia (32 \u00b0C). Hypothermia decreased hypoxia-induced rise in the extracellular lactate:pyruvate ratio, increased ATP\/ADP ratio and mitochondrial content, normalized lipid content, and improved the recovery of respiration after anoxia. Importantly, it was observed that in contrast to mild hypothermia, moderate and deep hypothermia interfere with HIF1 (hypoxia inducible factor 1)-dependent HRE (hypoxia response element) induction in hypoxia. This work also demonstrates that hypothermia alleviates reductive stress, a conceptually novel and largely overlooked phenomenon at the root of ischemia reperfusion injury.<\/jats:p>","DOI":"10.3390\/ijms231710108","type":"journal-article","created":{"date-parts":[[2022,9,6]],"date-time":"2022-09-06T05:17:23Z","timestamp":1662441443000},"page":"10108","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Hypothermia Alleviates Reductive Stress, a Root Cause of Ischemia Reperfusion Injury"],"prefix":"10.3390","volume":"23","author":[{"given":"Kattri-Liis","family":"Eskla","sequence":"first","affiliation":[{"name":"Institute of Biomedicine and Translational Medicine, Department of Physiology, University of Tartu, 50412 Tartu, Estonia"},{"name":"Center of Excellence for Genomics and Translational Medicine, University of Tartu, 50412 Tartu, Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans","family":"Vellama","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine and Translational Medicine, Department of Physiology, University of Tartu, 50412 Tartu, Estonia"},{"name":"Center of Excellence for Genomics and Translational Medicine, University of Tartu, 50412 Tartu, Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liisi","family":"Tarve","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine and Translational Medicine, Department of Physiology, University of Tartu, 50412 Tartu, Estonia"},{"name":"Center of Excellence for Genomics and Translational Medicine, University of Tartu, 50412 Tartu, Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hillar","family":"Eichelmann","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine and Translational Medicine, Department of Pathophysiology, University of Tartu, 50412 Tartu, Estonia"},{"name":"Institute of Technology, Faculty of Science and Technology, University of Tartu, 50412 Tartu, Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toomas","family":"Jagom\u00e4e","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine and Translational Medicine, Department of Physiology, University of Tartu, 50412 Tartu, Estonia"},{"name":"Center of Excellence for Genomics and Translational Medicine, University of Tartu, 50412 Tartu, Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rando","family":"Porosk","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine and Translational Medicine, Department of Biochemistry, University of Tartu, 50412 Tartu, Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vello","family":"Oja","sequence":"additional","affiliation":[{"name":"Institute of Technology, Faculty of Science and Technology, University of Tartu, 50412 Tartu, Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heikko","family":"R\u00e4mma","sequence":"additional","affiliation":[{"name":"Institute of Technology, Faculty of Science and Technology, University of Tartu, 50412 Tartu, Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nade\u017eda","family":"Peet","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine and Translational Medicine, Department of Pathophysiology, University of Tartu, 50412 Tartu, Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agu","family":"Laisk","sequence":"additional","affiliation":[{"name":"Institute of Technology, Faculty of Science and Technology, University of Tartu, 50412 Tartu, Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vallo","family":"Volke","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine and Translational Medicine, Department of Pathophysiology, 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