Colchicine attenuates kidney injury by modulating the NLRP3 inflammasome pathway.

BACKGROUND

Colchicine, a well-known anti-inflammatory drug, has emerged as a therapeutic option in various inflammatory diseases. However, its role in chronic kidney disease (CKD) remains unclear. This study aims to investigate the reno-protective effects of colchicine in an experimental CKD model and its potential role in modulating the NOD-like receptor, pyrin domain containing protein 3 (NLRP3) inflammasome pathway.

METHODS

A CKD animal model was established in C57BL/6 mice by feeding a 0.2% adenine-containing diet. Colchicine (0.3 mg/kg/day) or saline was administered intraperitoneally for 4 weeks. RNA sequencing of kidney tissue was performed to capture molecular signatures associated with the therapeutic mechanism of colchicine in CKD. In vitro, renal tubular epithelial cells (RTECs) were treated with transforming growth factor-β (TGF-β, 10 ng/ml) and bone marrow-derived macrophages (BMDMs) were exposed to p-cresol sulfate (PCS, 0.5 mM). Colchicine (0.1 μM for RTECs and 1.0 μM for BMDMs) was administered to evaluate its protective effects.

RESULTS

Colchicine treatment significantly reduced systemic inflammatory markers including tumor necrosis factor-α, interleukin-6, and interleukin-1β. In the kidney tissues of adenine-fed mice, prominent fibrotic change and macrophage infiltration were observed, both of which were significantly attenuated by colchicine treatment. These improvements were accompanied by reduced albuminuria and improved kidney function. RNA sequencing revealed that colchicine modulated key inflammatory pathways, including the nuclear factor-κB and NOD-like receptor signaling pathway. Notably, colchicine treatment significantly decreased the expression levels of NLRP3 inflammasome components in adenine-fed mice, TGF-β-treated RTECs and PCS-treated BMDMs. Mechanistically, colchicine inhibited the interaction between NLRP3 and apoptosis-associated speck-like protein containing a CARD in TGF-β-treated RTECs and PCS-treated BMDMs, resulting in decreased NLRP3 inflammasome assembly, as demonstrated by oligomerization cross-linking assay and proximity-ligation assay.

CONCLUSIONS

We demonstrated that colchicine can attenuate kidney injury and fibrosis in adenine-induced CKD mice by inhibiting NLRP3 inflammasome assembly and activation.