Abstract: Objective: To investigate the protective effect of ellagic acid (EA) on acute kidney injury induced by aristolochic acid I (AAI). Methods: Totally 40 Kunming mice, half male and half female, were randomly divided into four groups: healthy, model (AAI at 10 mg/(kg mb·d)), low-dosage EA (AAI at 10 mg/(kg mb·d) + EA 10 mg/(kg mb·d)), and high-dosage EA (AAI at 10 mg/(kg mb·d) + EA 30 mg/(kg mb·d)). Different dosages of EA were given to mice by gavage daily for 12 days. The acute kidney injury model was established by intraperitoneal injection of AAI starting from day 7. On day 12, all the mice were sacrificed for measurement of renal function indicators such as renal index, urine protein, urea nitrogen, and creatinine. Hematoxylin-eosin (HE) and Masson staining were performed to examine renal histopathological changes. Biochemical assay kits were used to determine oxidative stress indicators in the kidney including glutathione (GSH), total superoxide dismutase (T-SOD) and malondialdehyde (MDA). Enzyme linked immunosorbent assay (ELISA) and quantitative polymerase chain reaction (qPCR) were used to detect the levels of inflammatory factors in mice. Western blot and qPCR were used to detect the expression levels of nuclear factor (NF)-κB and NOD-like receptor protein 3 (NLRP3)-related factors in the kidney. Results: EA significantly improved renal function indexes and renal histopathological changes in mice with AAI-induced acute kidney injury, and restored oxidative stress indexes in the kidney to nearly normal levels. In addition, EA significantly down-regulated the levels of inflammatory factors including tumor necrosis factor (TNF)-α and interleukin (IL)-1β in the serum of the mouse model and reduced the transcription of the genes encoding TNF-α and IL-1β in the kidney. Further experiments revealed that EA considerably decreased the phosphorylation levels of inhibitor of NF-κB (IκB) α and NF-κB p65 proteins in the kidney of the mouse model (P < 0.05, P < 0.01), and inhibited the transcription and translation of NLRP3 inflammasome components including NLRP3, apoptosis-associated speck-like protein (ASC), caspase-1 and IL-1β. Conclusion: EA ameliorates AAI-induced acute kidney injury in mice possibly through a mechanism related to blocking of AAI-induced renal inflammation by interfering with the NF-κB/NLRP3 pathway.

Key words: aristolochic acid I; ellagic acid; acute kidney injury; inflammation; NF-κB/NLRP3 pathway