Details

Autor(en) / Beteiligte

• Hung, Tung-Wei
• Hsieh, Yi-Hsien
• Lee, Hsiang-Lin
• Ting, Yi-Hsuan
• Lin, Chu-Liang
• Chao, Wen-Wan

Titel

Renoprotective effect of rosmarinic acid by inhibition of indoxyl sulfate-induced renal interstitial fibrosis via the NLRP3 inflammasome signaling

Ist Teil von

• International immunopharmacology, 2024-06, Vol.135, p.112314-112314, Article 112314

Ort / Verlag

Netherlands: Elsevier B.V

Erscheinungsjahr

2024

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• [Display omitted] •Indoxyl sulfate (IS), exacerbates inflammation in chronic kidney disease (CKD)•Rosmarinic acid (RA) inhibits NLRP3 inflammasome activation and IS-induced renal fibrosis.•RA and MCC950 synergistically inhibit NLRP3 signaling in a mouse model of CKD.•RA’s mechanism involves the PI3K/AKT and TGF-β/Smad signaling pathways. We previously reported that rosmarinic acid (RA) ameliorated renal fibrosis in a unilateral ureteral obstruction (UUO) murine model of chronic kidney disease. This study aimed to determine whether RA attenuates indoxyl sulfate (IS)-induced renal fibrosis by regulating the activation of the NLRP3 inflammasome/IL-1β/Smad circuit. We discovered the NLRP3 inflammasome was activated in the IS treatment group and downregulated in the RA-treated group in a dose-dependent manner. Additionally, the downstream effectors of the NLRP3 inflammasome, cleaved-caspase-1 and cleaved-IL-1β showed similar trends in different groups. Moreover, RA administration significantly decreased the ROS levels of reactive oxygen species in IS-treated cells. Our data showed that RA treatment significantly inhibited Smad-2/3 phosphorylation. Notably, the effects of RA on NLRP3 inflammasome/IL-1β/Smad and fibrosis signaling were reversed by the siRNA-mediated knockdown of NLRP3 or caspase-1 in NRK-52E cells. In vivo, we demonstrated that expression levels of NLRP3, c-caspase-1, c-IL-1β, collagen I, fibronectin and α-SMA, and TGF- β 1 were downregulated after treatment of UUO mice with RA or RA + MCC950. Our findings suggested RA and MCC950 synergistically inhibited UUO-induced NLRP3 signaling activation, revealing their renoprotective properties and the potential for combinatory treatment of renal fibrosis and chronic kidney inflammation.