{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:44:59Z","timestamp":1760060699813,"version":"build-2065373602"},"reference-count":84,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,13]],"date-time":"2025-09-13T00:00:00Z","timestamp":1757721600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Italian Ministry of Health","award":["08054218"],"award-info":[{"award-number":["08054218"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Proprotein Convertase Subtilisin\/Kexin type 9 PCSK9 inhibitors (PCSK9i) are a novel class of cholesterol-lowering agents that also offer protection against tissue ischemia by reducing apoptosis, pyroptosis, and myocardial infarct size. This study evaluated the effects of the PCSK9 inhibitor PEP 2-8 during hypothermic perfusion (HP) in a rat model of donation after circulatory death (DCD) kidney transplantation. DCD kidneys were perfused at 4 \u00b0C for six hours with either Perf-Gen solution alone (control) or Perf-Gen supplemented with PEP 2-8. Glucose and lactate dehydrogenase (LDH) levels were measured at baseline and after six hours (T6h). At T6h, kidneys were evaluated for ischemic injury, tubular cell proliferation, apoptosis, nitrotyrosine (N-Tyr) staining, tissue ATP and LDH levels, and gene expression of PCSK9 and NOX4. Metabolomic profiling was also performed. PEP 2-8 treatment significantly reduced PCSK9 expression, decreased tubular ischemic injury and necrosis, and lowered LDH release. Treated kidneys showed enhanced tubular cell proliferation, reduced apoptosis, and diminished oxidative stress, indicated by decreased N-Tyr staining and NOX4 expression. Energy metabolism was improved, with higher tissue ATP and glucose levels observed in the PEP 2-8 group. Metabolomic analysis further supported the antioxidant effects of PEP 2-8. This is the first study to demonstrate that PEP 2-8 administered during pre-transplant hypothermic perfusion provides renal protection by improving energy metabolism and reducing oxidative stress in the context of ischemic injury.<\/jats:p>","DOI":"10.3390\/ijms26188937","type":"journal-article","created":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T07:33:02Z","timestamp":1758007982000},"page":"8937","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Pre-Clinical Study on the Use of the Proprotein Convertase Subtilisin\/Kexin Type 9 Inhibitor PEP 2-8 to Mitigate Ischemic Injury in a Rat Marginal Donor Model"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1439-7662","authenticated-orcid":false,"given":"Maria Antonietta","family":"Grignano","sequence":"first","affiliation":[{"name":"Unit of Nephrology, Dialysis and Transplantation, Fondazione I.R.C.C.S. 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Policlinico San Matteo, 27100 Pavia, Italy"},{"name":"Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiara","family":"Barisione","sequence":"additional","affiliation":[{"name":"Department of Surgical and Integrated Diagnostic Sciences, University of Genoa, 16132 Genova, Italy"},{"name":"IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1590-7196","authenticated-orcid":false,"given":"Caterina","family":"Ivaldo","sequence":"additional","affiliation":[{"name":"Department of Surgical and Integrated Diagnostic Sciences, University of Genoa, 16132 Genova, Italy"},{"name":"IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniela","family":"Verzola","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Medical Specialties (DIMI), University of Genoa, 16132 Genova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0936-1104","authenticated-orcid":false,"given":"Noemi","family":"Rumeo","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Medical Specialties (DIMI), University of Genoa, 16132 Genova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefano","family":"Malabarba","sequence":"additional","affiliation":[{"name":"Transplant Unit, Fondazione I.R.C.C.S. 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Policlinico San Matteo, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5651-149X","authenticated-orcid":false,"given":"Paolo","family":"Iadarola","sequence":"additional","affiliation":[{"name":"Department of Biology and Biotechnologies \u201cL. Spallanzani\u201d, University of Pavia, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8513-8505","authenticated-orcid":false,"given":"Tefik","family":"Islami","sequence":"additional","affiliation":[{"name":"Unit of Nephrology, Dialysis and Transplantation, Fondazione I.R.C.C.S. Policlinico San Matteo, 27100 Pavia, Italy"},{"name":"Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7870-2094","authenticated-orcid":false,"given":"Eleonora Francesca","family":"Pattonieri","sequence":"additional","affiliation":[{"name":"Unit of Nephrology, Dialysis and Transplantation, Fondazione I.R.C.C.S. Policlinico San Matteo, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8576-694X","authenticated-orcid":false,"given":"Gabriele","family":"Ceccarelli","sequence":"additional","affiliation":[{"name":"Human Anatomy Unit, Department of Public Health, Experimental and Forensic Medicine, University of Pavia, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniela","family":"Picciotto","sequence":"additional","affiliation":[{"name":"Unit of Nephrology, Dialysis and Transplantation, IRCCS Policlinico San Martino, 16132 Genova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovanni","family":"Pratesi","sequence":"additional","affiliation":[{"name":"Department of Surgical and Integrated Diagnostic Sciences, University of Genoa, 16132 Genova, Italy"},{"name":"IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4219-7043","authenticated-orcid":false,"given":"Francesca","family":"Viazzi","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Medical Specialties (DIMI), University of Genoa, 16132 Genova, Italy"},{"name":"Unit of Nephrology, Dialysis and Transplantation, IRCCS Policlinico San Martino, 16132 Genova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emma Diletta","family":"Stea","sequence":"additional","affiliation":[{"name":"Unit of Nephrology, Dialysis and Transplantation, Fondazione I.R.C.C.S. 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