Farnesoid X Receptor Alleviates Cisplatin-Induced Kidney Inflammatory Injury by Inhibiting Tlr4/NF-κB Pathway

Area of Science:

• Nephrology
• Immunology
• Pharmacology

Background:

• Inflammatory responses are central to cisplatin-induced acute kidney injury (AKI).
• Farnesoid X receptor (FXR) shows potential in mitigating kidney dysfunction, but its anti-inflammatory mechanisms in AKI are not fully understood.

Purpose of the Study:

• To investigate whether FXR activation reduces cisplatin-induced AKI by modulating renal inflammation.
• To elucidate the specific molecular pathways involved in FXR's protective effects against AKI.

Main Methods:

• A mouse model of cisplatin-induced AKI was utilized.
• Kidney tissues were analyzed for immune cell infiltration, pro-inflammatory cytokine expression (IL-1β, IL-6, CXCLs, CCL2), and the Tlr4/NF-κB pathway.
• RNA sequencing was performed to identify inflammation-related gene expression changes.
• In vitro studies used renal tubular epithelial cells treated with cisplatin and GW4064 (FXR agonist).

Main Results:

• Cisplatin induced significant kidney inflammation, characterized by increased immune cell infiltration and elevated pro-inflammatory mediators.
• FXR activation with GW4064 attenuated inflammation, reduced immune cell infiltration, and suppressed the Tlr4/NF-κB pathway, thereby alleviating kidney injury.
• Proximal tubule-specific FXR knockout exacerbated renal inflammation and NF-κB activity.
• In vitro, GW4064 decreased pro-inflammatory cytokine production, inhibited Tlr4/NF-κB signaling, and reduced apoptosis in cisplatin-treated cells.

Conclusions:

• FXR activation significantly alleviates cisplatin-induced renal inflammation by suppressing the Tlr4/NF-κB signaling pathway.
• FXR plays a crucial role in protecting against cisplatin-induced AKI through its anti-inflammatory effects.
• FXR agonists represent a promising therapeutic avenue for managing cisplatin-induced AKI.