Ellagic Acid Protects Against Acute Stress-Induced Kidney Damage in Rats by Regulating the SIRT1/Nrf2 Signaling Pathway

Abstract

Ellagic acid displays multiple biological and pharmacological effects. Here, we explore its protective role against acute stress (AS)–induced kidney damage. We established the AS model through excessive swimming (15 min) and restraint stress (3 h), which decreased movement and exploratory behaviors in the open field test. Pretreatment with ellagic acid (10 mg/kg, orally for 14 days) reversed these changes and improved histopathological lesion and renal dysfunction. Moreover, ellagic acid alleviated AS-induced renal oxidative stress and apoptosis. This was evidenced by increased superoxide dismutase, glutathione, total antioxidant capacity, and catalase, alongside decreased levels of reactive oxygen species, malondialdehyde, apoptotic cells, caspase-3, and the Bax/Bcl-2 protein ratio. Additionally, ellagic acid mitigated AS-induced renal inflammation by lowering the nuclear factor kappa B (NF-κB) level, granulocyte percentage, myeloperoxidase activity, and tumor necrosis factor–α content. Notably, molecular docking suggested a stable interaction between ellagic acid and sirtuin 1 (SIRT1). Ellagic acid significantly enhanced the expression levels of SIRT1, nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1, and NAD(P)H oxidoreductase 1 proteins. Importantly, the afore-mentioned effects of ellagic acid were substantially diminished by the SIRT1 inhibitor EX527. Correlation analysis showed that the SIRT1/Nrf2 signaling pathway was inversely related to oxidative stress, apoptosis, inflammation, and kidney damage. Collectively, these findings indicate that ellagic acid mitigates AS-induced renal damage by stimulating the SIRT1/Nrf2 signaling pathway, suppressing oxidative stress, inhibiting apoptosis, and attenuating NF-κB-mediated inflammation.