Linderalactone mitigates diabetic renal injury by inhibiting macrophage inflammation via the Dectin1/Syk/CARD9/IRF5/NF-κB pathway

Background: Inflammation plays an essential role in the pathogenesis of diabetic nephropathy (DN). Linderalactone (LNL), as a natural sesquiterpene lactone, has been discovered to have anti-inflammatory activation. However, the effects of linderalactone on diabetes-associated renal damage remain unclear.

Methods: This study investigated the effects of LNL on renal function and inflammation in diabetic mice. Renal function, Collagen deposition, and fibrosis were assessed. RNA-sequencing was performed to identify molecular pathways affected by LNL. The Dectin1-related pathway was analyzed in kidney tissues and RAW264.7 cells. Dectin1-deficient and Dectin1-overexpressing models were used to confirm the mechanism of LNL.

Results: LNL improved renal function, reduced Collagen deposition and fibrosis in diabetic mice without affecting blood glucose levels. RNA-sequencing revealed that LNL primarily impacted the Dectin1 pathway. It inhibited the Dectin1/Syk/CARD9/IRF5/NF-κB pathway, reduced macrophage and neutrophil infiltration, and suppressed inflammatory cytokine expression. Dectin1 knockdown mimicked these effects, while Dectin1 overexpression reversed them.

Conclusions: LNL alleviates DN via suppression of macrophage inflammation by mediating the Dectin1/Syk/CARD9/IRF5/NF-κB signaling pathway, highlighting its potential as a therapeutic agent for diabetes-associated renal injury.

Diabetic nephropathy; Inflammation; Linderalactone.