Tabriz University of Medical Sciences Advanced Pharmaceutical Bulletin 2228-5881 16 1 2026 05 19 Eplerenone Attenuates Hepatic Oxidative Stress and Mitochondrial Dysfunction Following Renal Ischemia-Reperfusion Injury in Rats 139 148 10.34172/apb.025.45926 EN Alireza Barati https://orcid.org/0000-0003-2922-2101 Seyed Mohammadmahdi Meybodi Kimia Moradi Sana Nouraei Mohammad Bakhshi Soheila Montazersaheb https://orcid.org/0000-0001-5010-7293 Sepideh Zununi Vahed https://orcid.org/0000-0003-0179-4562 Journal Article 10.34172/apb.025.45926 2025 06 07 2025 12 17 Purpose: Acute kidney injury (AKI) is frequently complicated by systemic manifestations, including hepatic dysfunction, largely due to ischemia-reperfusion (I/R) injury. This study investigated the hepatoprotective effects of eplerenone, a selective aldosterone receptor antagonist, in a rat model of renal I/R. Methods: Male Wistar rats (n=24) were randomly divided into four groups: sham, I/R, eplerenone+I/R, and eplerenone alone. A single intraperitoneal dose of eplerenone (100 mg/kg) was administered one hour before ischemia induction. Hepatic injury was evaluated by histopathology, liver function enzymes (ALT, AST, ALP), oxidative stress parameters, sirtuins, and key mitochondrial and apoptotic signaling proteins. Results: Renal I/R resulted in significant hepatic injury, characterized by histological alterations, increased liver enzymes, oxidative stress, and activation of inflammatory and apoptotic pathways. Pretreatment with eplerenone markedly improved hepatic outcomes by lowering ALT, AST, and ALP levels, preserving liver morphology, suppressing NF-κB and caspase-3 expression, and enhancing antioxidant and mitochondrial protective mechanisms, particularly through Nrf2 and Sirt-3/PGC-1α/Opa-1 pathways. The results indicated that eplerenone administration significantly improved liver function and histology following kidney I/R injury. Caspase-3 and NF-κB levels were downregulated following eplerenone administration. It also elevated the antioxidant capacity and protein levels of Nrf-2, HSP-70 (P<0.001), mitochondrial biogenesis factor (PGC-1α), sirtuin-1 (P<0.05), and dynamics factor (Opa-1, P<0.001), while decreasing Drp-1 levels (P<0.05) in the liver after kidney I/R injury. Conclusion: Eplerenone demonstrated strong hepatoprotective effects against renal I/R-induced liver injury. Its antioxidant, anti-inflammatory, and mitochondria-stabilizing actions highlight its potential as a therapeutic agent for preventing hepatic dysfunction associated with AKI and underline the importance of targeting distant organ injury in acute renal pathophysiology.