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Acute kidney injury (AKI) is a critical complication of sepsis. Various pathways, especially signaling through Toll-like receptors (TLRs) and the nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome, contribute to inflammation and tissue damage. Cilastatin, a renal dehydropeptidase I inhibitor, has shown promise in protecting against AKI induced by nephrotoxic drugs. This study assessed cilastatin\u2019s effectiveness in preventing AKI and inflammation caused by sepsis and its impact on survival. Sepsis was induced in male Sprague-Dawley rats using the cecal ligation puncture (CLP) model, with four groups: sham (control), CLP, sham + cilastatin, and CLP + cilastatin. Cilastatin (150 mg\/kg) was administered immediately and 24 h after sepsis induction. Kidney injury was evaluated 48 h later by assessing serum creatinine, blood urea nitrogen, glomerular filtration rate, proteinuria, kidney injury molecule-1 levels, and renal morphology. Inflammatory and fibrotic biomarkers, particularly related to the TLR4 and NLRP3 pathways, were also measured. Cilastatin treatment prevented kidney dysfunction, reduced inflammatory markers, and improved survival by 33%. These results suggest that cilastatin could be a beneficial therapeutic strategy for sepsis-related AKI, improving outcomes and reducing mortality.<\/jats:p>","DOI":"10.3390\/ijms26167927","type":"journal-article","created":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T16:22:33Z","timestamp":1755534153000},"page":"7927","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Cilastatin Attenuates Acute Kidney Injury and Reduces Mortality in a Rat Model of Sepsis"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3514-4616","authenticated-orcid":false,"given":"Mar\u00eda \u00c1ngeles","family":"Gonz\u00e1lez-Nicol\u00e1s","sequence":"first","affiliation":[{"name":"Renal Physiopathology Laboratory, Department of Nephrology, Instituto de Investigaci\u00f3n Sanitaria Gregorio Mara\u00f1\u00f3n, Hospital General Universitario Gregorio Mara\u00f1\u00f3n, 28007 Madrid, Spain"},{"name":"Department of Physiology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain"},{"name":"RICORS2040, 28007 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blanca","family":"Humanes","sequence":"additional","affiliation":[{"name":"Renal Physiopathology Laboratory, Department of Nephrology, Instituto de Investigaci\u00f3n Sanitaria Gregorio Mara\u00f1\u00f3n, Hospital General Universitario Gregorio Mara\u00f1\u00f3n, 28007 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel","family":"Herrero","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, Hospital Universitario de Getafe, 28905 Madrid, Spain"},{"name":"CIBER de Enfermedades Respiratorias, Instituto de Investigaci\u00f3n Carlos III, 28029 Madrid, Spain"},{"name":"Fundaci\u00f3n de Investigaci\u00f3n Biom\u00e9dica del Hospital Universitario de Getafe, 28905 Madrid, Spain"},{"name":"Clinical Department, Faculty of Health, Medicine and Sports, Universidad Europea, 28670 Madrid, Spain"},{"name":"Department of Bioengineering, School of Biomedical Engineering, Universidad Carlos III, 28903 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3315-7931","authenticated-orcid":false,"given":"Mario","family":"Arenillas","sequence":"additional","affiliation":[{"name":"Animal Medicine and Surgery Department, Complutense University of Madrid, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz","family":"L\u00f3pez","sequence":"additional","affiliation":[{"name":"Department of Pathology, Hospital General Universitario Gregorio Mara\u00f1\u00f3n, 28007 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Ferruelo","sequence":"additional","affiliation":[{"name":"CIBER de Enfermedades Respiratorias, Instituto de Investigaci\u00f3n Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7679-9187","authenticated-orcid":false,"given":"Jos\u00e9 \u00c1ngel","family":"Lorente","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, Hospital Universitario de Getafe, 28905 Madrid, Spain"},{"name":"CIBER de Enfermedades Respiratorias, Instituto de Investigaci\u00f3n Carlos III, 28029 Madrid, Spain"},{"name":"Fundaci\u00f3n de Investigaci\u00f3n Biom\u00e9dica del Hospital Universitario de Getafe, 28905 Madrid, Spain"},{"name":"Clinical Department, Faculty of Health, Medicine and Sports, Universidad Europea, 28670 Madrid, Spain"},{"name":"Department of Bioengineering, School of Biomedical Engineering, Universidad Carlos III, 28903 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1095-679X","authenticated-orcid":false,"given":"Alberto","family":"L\u00e1zaro","sequence":"additional","affiliation":[{"name":"Renal Physiopathology Laboratory, Department of Nephrology, Instituto de Investigaci\u00f3n Sanitaria Gregorio Mara\u00f1\u00f3n, Hospital General Universitario Gregorio Mara\u00f1\u00f3n, 28007 Madrid, Spain"},{"name":"Department of Physiology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain"},{"name":"RICORS2040, 28007 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2063","DOI":"10.1056\/NEJMra1208623","article-title":"Severe sepsis and septic shock","volume":"369","author":"Angus","year":"2013","journal-title":"N. 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