Dose‐Dependent Hepato–Renal Histopathology and Inflammatory Signaling Changes After Subacute Oral Resveratrol Exposure in Healthy Female Rats

Resveratrol is widely studied for its anti-inflammatory properties, yet the dose-response relationship between its molecular effects and potential organ toxicity in healthy animals remains poorly characterized. This study investigated whether the doses that suppress NF-κB signaling overlap with those causing measurable hepato-renal injury in healthy female rats. Rats received saline control, vehicle control (10% DMSO in saline), or resveratrol at 5, 10, 20, or 30 mg/kg by oral gavage every 72 h for 21 days, corresponding to seven doses. Plasma hepatic and renal biochemistry and oxidative stress markers were measured using standardized assays. NF-κB p65 DNA-binding activity was quantified in liver nuclear extracts using ELISA. Liver, kidney, heart, and spleen tissues were processed for H&E histology with blinded semiquantitative scoring and ImageJ-based morphometry. Correlations between dose and biochemical parameters were assessed using Spearman's rank correlation on individual-animal data. Resveratrol produced a dose-dependent pattern of organ injury. Mild histological changes were observed at 5-10 mg/kg, whereas more pronounced degenerative and inflammatory alterations were observed at 20-30 mg/kg in the liver and kidney. Plasma AST showed a significant dose-related increase after FDR correction (q = 0.0445), while ALT, ALP, and urea showed nominal increases that did not remain significant after correction. Hepatic NF-κB p65 DNA-binding activity was significantly suppressed in a dose-dependent manner (q = 0.049), with the greatest suppression at 20-30 mg/kg, the same dose range in which histological injury was most evident. Exploratory individual-level analysis suggested that greater NF-κB suppression tended to co-occur with higher hepatic lesion scores. Plasma oxidative-stress markers showed no consistent dose-related differences. These findings indicate that, in healthy rats, the dose range associated with effective NF-κB modulation (≥ 20 mg/kg) overlaps with the threshold for measurable hepato-renal injury. This overlap defines a narrow therapeutic window and highlights the importance of dose justification and safety monitoring in resveratrol supplementation and clinical studies.