THBS1-mediated macrophage polarization in the pathogenesis of sepsis-induced acute kidney injury

Objective This investigation seeks to examine the involvement of Thrombospondin 1 (THBS1) in sepsis-related acute renal dysfunction, focusing specifically on how it influences macrophage phenotypic switching and programmed cell death through pyroptosis, while evaluating its potential as a novel treatment approach. Methods This study employed RNA sequencing technology for gene expression profiling to investigate transcriptomic alterations in patients with sepsis-associated acute kidney injury. An experimental murine sepsis model was established, and THBS1 gene expression was suppressed using small interfering RNA-mediated gene knockout technology. Methods such as immunofluorescence microscopy were employed to assess macrophage phenotypic transformation and renal injury. In vitro experiments involved the isolation and culture of primary macrophages, which were then polarized by lipopolysaccharide (LPS) and co-cultured with renal tubular epithelial cells (HK-2 cell line) to investigate the mechanisms underlying programmed cell death. Results THBS1 expression showed marked increases in both human sepsis cases and murine models, promoting polarization toward M1-type macrophages. Inhibition of THBS1 led to attenuated inflammatory responses, decreased oxidative stress, mitigated renal injury, and promoted macrophage differentiation toward the M2 phenotype. Macrophage-derived THBS1, stimulated by LPS exposure, triggered pyroptotic cell death in HK-2 renal tubular cells. Downregulation of THBS1 enhanced macrophage mitochondrial performance through multiple mechanisms: suppressing succinate dehydrogenase function, normalizing mitochondrial transmembrane potential, lowering reactive oxygen species production, and correcting metabolic abnormalities. Discussion The protein THBS1 has been identified as a critical mediator in sepsis-induced acute kidney injury, primarily through its ability to promote M1 macrophage polarization and trigger pyroptotic cell death. Experimental evidence demonstrates that suppressing THBS1 activity leads to significant attenuation of renal damage and enhancement of macrophage mitochondrial performance. These observations indicate THBS1's potential as a valuable intervention point for managing sepsis-associated kidney dysfunction, with its effects being mediated via macrophage phenotype modulation and pyroptosis regulation.