Papaverine Mitigates Acute Kidney Injury in Feces-Induced Polymicrobial Sepsis Through Regulation of the HMGB1–RAGE Axis

Background and Objectives: Sepsis-associated acute kidney injury (SA-AKI) is driven by exaggerated inflammation and oxidative stress, with the HMGB1–RAGE 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–RAGE-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-α, CRP), oxidative stress (MDA), circulating sRAGE levels, renal NF-κB 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-α, 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-κB 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–oxidative cascade contributing to SA-AKI. Papaverine confers dose-dependent renoprotection by suppressing HMGB1–RAGE signaling, attenuating NF-κB activation, reducing oxidative stress, and preserving renal structure and function. Targeting the HMGB1–sRAGE axis may represent a promising therapeutic strategy in sepsis-associated renal injury.