Loganetin protects against rhabdomyolysis-induced acute kidney injury by modulating the Toll-like receptor 4 signaling pathway.

BACKGROUND AND PURPOSE: Acute kidney injury (AKI) is a rapid renal dysfunctional disease, for which no effective drugs or therapies are available to improve prognosis. Loganetin is a natural product with unknown bioactivities. Here we identified a new protective effect and mechanism of Loganetin in rhabdomyolysis-induced AKI mice model.

EXPERIMENTAL APPROACH: AKI was induced using glycerol by intramuscular injection in mice models. Thirty minutes, 24 h and 48 h after injection of glycerol, the mice received 2 and 18 mg/kg of Loganetin i.p respectively. Then mice blood and kidney were collected for various biochemical and histopathological studies. Mechanistic studies on modulation of AKI by Loganetin were performed using HK-2 cells and TLR4-knockout mice.

KEY RESULTS: In Loganetin treatment group, kidney damage and mice mortality rate were declined, blood urea nitrogen (BUN) and serum creatinine (CREA) were much lower. Loganetin prevented damage to the tubular structures induced by glycerol and decreased apoptotic cells at the corticomedullary junction. In HK-2 cells, Loganetin could inhibit NF-κB pathway and pro-apoptotic genes expression. However, TLR4 was silenced by a specific shRNA, the inhibitory effect of Loganetin in HK-2 cells vanished. Loganetin also down regulated the expression of inflammation factors by suppressing TLR4 activity.

CONCLUSION AND IMPLICATIONS: All the results suggested that TLR4 plays a critical role in AKI development, and Loganetin ameliorates AKI by inhibiting TLR4 activity and blocking the JNK/p38 pathway, which provides a new strategy for AKI treatment.