Geniposide activates the NLRP3 inflammasome pathway to induce nephrotoxicity by regulating FXR/PERK/TXNIP pathways

Fructus Gardeniae, a widely used traditional Chinese medicine that also serves as food, contains geniposide as its active ingredient. Current research indicates that high doses of geniposide can cause nephrotoxicity in rats. This study investigates the nephrotoxicity induced by geniposide and preliminarily explores its underlying mechanisms. Male SD rats were orally administered geniposide (200 mg/kg), geniposide (400 mg/kg), and geniposide + obeticholic acid (OCA) (25 mg/kg) for 1 week consecutively. The results indicate that geniposide induces nephrotoxicity, manifested by elevated levels of blood urea nitrogen, creatinine, KIM-1, and NGAL, along with increased renal histopathological damage. Additionally, in all geniposide dose groups, the mRNA and protein expression levels of FXR were significantly downregulated, while those of NLRP3 and Caspase-1 were upregulated. The addition of the FXR receptor agonist OCA alleviated the nephrotoxicity induced by geniposide, as evidenced by reduced levels of urea nitrogen, creatinine, KIM-1, and NGAL, as well as mitigated renal histopathological damage. The protein expression levels of ASC, cleaved IL-1β and cleaved Caspase-1 were detected by Western Blot. RT-qPCR and Western blot experiments revealed a significant upregulation of FXR mRNA and protein levels, while the mRNA and protein expression of endoplasmic reticulum stress-related proteins PERK and TXNIP, NLRP3 and Caspase-1, were downregulated. These results confirm that geniposide can induce nephrotoxicity, and the FXR/PERK/TXNIP/NLRP3 signaling pathway is involved.