{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T19:51:56Z","timestamp":1784317916418,"version":"3.55.0"},"reference-count":61,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T00:00:00Z","timestamp":1774396800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Background and Objectives: Sepsis-associated acute kidney injury (SA-AKI) is driven by exaggerated inflammation and oxidative stress, with the HMGB1\u2013RAGE axis playing a pivotal role in amplifying tissue damage. This study aimed to investigate the renoprotective effects of papaverine in a feces-induced peritonitis (FIP) model of sepsis and to explore its impact on HMGB1\u2013RAGE-mediated inflammatory and oxidative pathways. Materials and Methods: Sepsis was induced in male Wistar rats by intraperitoneal injection of fecal slurry (1 g\/kg). Animals were treated with papaverine (20 or 40 mg\/kg, i.p.) one hour after FIP induction and evaluated at 24 h. Renal function (BUN, creatinine, lactate), inflammatory markers (HMGB1, TNF-\u03b1, CRP), oxidative stress (MDA), circulating sRAGE levels, renal NF-\u03baB levels, and histopathological injury scores were assessed. Results: The FIP model resulted in an early mortality rate of 20% and produced marked renal histopathological alterations. Biochemically, FIP increased plasma HMGB1, TNF-\u03b1, CRP, MDA, BUN, creatinine, and lactate levels while decreasing sRAGE. Papaverine treatment dose-dependently reduced inflammatory and oxidative markers, restored sRAGE levels, improved renal function parameters, and attenuated histopathological injury. In addition, renal NF-\u03baB levels were significantly elevated in the FIP group compared to controls and were dose-dependently reduced following papaverine treatment. Conclusions: FIP-induced sepsis activates an HMGB1-driven inflammatory\u2013oxidative cascade contributing to SA-AKI. Papaverine confers dose-dependent renoprotection by suppressing HMGB1\u2013RAGE signaling, attenuating NF-\u03baB activation, reducing oxidative stress, and preserving renal structure and function. Targeting the HMGB1\u2013sRAGE axis may represent a promising therapeutic strategy in sepsis-associated renal injury.<\/jats:p>","DOI":"10.3390\/medicina62040621","type":"journal-article","created":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T12:05:49Z","timestamp":1775563549000},"page":"621","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Papaverine Mitigates Acute Kidney Injury in Feces-Induced Polymicrobial Sepsis Through Regulation of the HMGB1\u2013RAGE Axis"],"prefix":"10.3390","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1358-0158","authenticated-orcid":false,"given":"Mehmet Fatih","family":"Dasiran","sequence":"first","affiliation":[{"name":"Department of General Surgery, Faculty of Medicine, Tokat Gaziosmanpasa University, Tokat 60250, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6333-4919","authenticated-orcid":false,"given":"Ahmet","family":"Akba\u015f","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Faculty of Medicine, Karadeniz Technical University, Trabzon 61080, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2480-1374","authenticated-orcid":false,"given":"Bakiye","family":"Akba\u015f","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Faculty of Medicine, Karadeniz Technical University, Trabzon 61080, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2448-2337","authenticated-orcid":false,"given":"Ejder Saylav","family":"Bora","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, Faculty of Medicine, Izmir Katip \u00c7elebi University, \u0130zmir 35100, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4272-0562","authenticated-orcid":false,"given":"Hatice","family":"Aygun","sequence":"additional","affiliation":[{"name":"Neuroscience Laboratory, BAMER, Biruni University, Istanbul 34015, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5427-8428","authenticated-orcid":false,"given":"Oytun","family":"Erbas","sequence":"additional","affiliation":[{"name":"BAMER, Biruni University, Istanbul 34015, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/S0140-6736(19)32989-7","article-title":"Global, regional, and national sepsis incidence and mortality, 1990\u20132017: Analysis for the Global Burden of Disease Study","volume":"395","author":"Rudd","year":"2020","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1001\/jama.2016.0287","article-title":"The third international consensus definitions for sepsis and septic shock (Sepsis-3)","volume":"315","author":"Singer","year":"2016","journal-title":"JAMA"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e1063","DOI":"10.1097\/CCM.0000000000005337","article-title":"Surviving sepsis campaign: International guidelines for management of sepsis and septic shock 2021","volume":"49","author":"Evans","year":"2021","journal-title":"Crit. 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