Pathology, research and practice · 2025
CSB6B attenuates renal inflammation and fibrosis by inhibiting the activation of NLRP3 inflammasome through the NLRP3/Caspase-1/GSDMD/IL-1β signaling pathway.
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Chen Shuo, Zhu Yonghong, Chen Tong, Xu Yanyan, Fan Qiuling
Аннотация
CONTEXT: Diabetic Kidney Disease (DKD) is a significant complication and leading cause of death in both type 1 and type 2 diabetes, as well as the primary cause of chronic kidney disease. Macrophage migration inhibitory factor (MIF) activates the NLRP3 inflammasome. Chicago sky blue 6B (CSB6B) is a MIF inhibitor with therapeutic potential in various inflammatory diseases, but its effect on DKD remains unexplored.
MATERIALS AND METHODS: HK-2 cell was used as the in vitro cell model. For the in vivo animal model, The db/db mice were randomly divided into three subgroups: the diabetic nephropathy model group, the low-dose CSB6B intervention group (2 mg/kg), and the high-dose CSB6B intervention group (8 mg/kg), with drug administration via intraperitoneal injection twice weekly for 12 weeks. CCK-8 assessed CSB6B toxicity, while qPCR measured MIF mRNA expression. Western blot, immunohistochemistry and ELISA detected protein expression level, and LDH release assessed membrane integrity. Histological analysis evaluated renal pathological changes.
RESULTS: CSB6B significantly inhibited the secretion of inflammatory cytokines interleukin-1β (IL-1β) and TGF-β1 from high-glucose-stimulated HK-2 cells without affecting their viability. CSB6B effectively inhibited the expression and secretion of MIF in high-glucose-stimulated HK-2 cells, down-regulated the expression of NLRP3, suppressed the activation of NLRP3 inflammasomes, reduced the production of cell pyroptosis-related proteins, and significantly decreased collagen I and FN expression. CSB6B treatment significantly reduced the body weight, blood glucose, blood creatinine, urine ACR, and NGAL of db/db mice, and improved the pathological damage of diabetic nephropathy. CSB6B effectively reduced the expression level of MIF protein in diabetic nephropathy mice, down-regulated the expression of NLRP3, Caspase-1, GSDMD, IL-1β, Collagen I and FN in the renal cortex of diabetic nephropathy mice.
CONCLUSIONS: CSB6B mitigated DKD by inhibiting the NLRP3/Caspase-1/GSDMD pyroptosis signaling pathway, suppressed cell pyroptosis, reduced cytokine secretion, and decreasd extracellular matrix accumulation. CSB6B showed promise as a potential therapeutic for DKD.
MATERIALS AND METHODS: HK-2 cell was used as the in vitro cell model. For the in vivo animal model, The db/db mice were randomly divided into three subgroups: the diabetic nephropathy model group, the low-dose CSB6B intervention group (2 mg/kg), and the high-dose CSB6B intervention group (8 mg/kg), with drug administration via intraperitoneal injection twice weekly for 12 weeks. CCK-8 assessed CSB6B toxicity, while qPCR measured MIF mRNA expression. Western blot, immunohistochemistry and ELISA detected protein expression level, and LDH release assessed membrane integrity. Histological analysis evaluated renal pathological changes.
RESULTS: CSB6B significantly inhibited the secretion of inflammatory cytokines interleukin-1β (IL-1β) and TGF-β1 from high-glucose-stimulated HK-2 cells without affecting their viability. CSB6B effectively inhibited the expression and secretion of MIF in high-glucose-stimulated HK-2 cells, down-regulated the expression of NLRP3, suppressed the activation of NLRP3 inflammasomes, reduced the production of cell pyroptosis-related proteins, and significantly decreased collagen I and FN expression. CSB6B treatment significantly reduced the body weight, blood glucose, blood creatinine, urine ACR, and NGAL of db/db mice, and improved the pathological damage of diabetic nephropathy. CSB6B effectively reduced the expression level of MIF protein in diabetic nephropathy mice, down-regulated the expression of NLRP3, Caspase-1, GSDMD, IL-1β, Collagen I and FN in the renal cortex of diabetic nephropathy mice.
CONCLUSIONS: CSB6B mitigated DKD by inhibiting the NLRP3/Caspase-1/GSDMD pyroptosis signaling pathway, suppressed cell pyroptosis, reduced cytokine secretion, and decreasd extracellular matrix accumulation. CSB6B showed promise as a potential therapeutic for DKD.