Regulation of Inflammatory Responses and Apoptosis: sgp130Fc as a Potential Therapeutic Agent for Sepsis-Associated Kidney Injury.

OBJECTIVE

This study aims to evaluate the therapeutic potential and underlying mechanisms of sgp130Fc, a selective inhibitor of interleukin-6 (IL-6) trans-signaling, in mitigating sepsis-associated kidney injury (SAKI).

METHODS

A cohort of 60 patients was stratified into three groups: Sepsis group (n = 20), SAKI Stages I-II group (n = 20), and SAKI Stage III group (n = 20). A positive correlation was observed between acute kidney injury severity and IL-6 levels. In vivo , sepsis was induced in male C57BL/6J mice via cecal ligation and puncture. The therapeutic effects of sgp130Fc, a selective inhibitor of IL-6 trans-signaling, were investigated. Transcriptomic analysis (RNA-seq) of renal tissue from septic mice identified differentially expressed genes. Gene ontology (GO) enrichment analysis confirmed significant enrichment of inflammation-related pathways, further validated using hypergeometric testing with an inflammation-specific gene set. Expression of downstream signaling molecules [signal transducer and activator of transcription 3 (STAT3), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)], apoptosis-related proteins [B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax)], and renal injury biomarkers [kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL)] was also assessed.

RESULTS

Administration of sgp130Fc attenuated SAKI through inhibition of IL-6/sIL-6R signaling and modulation of the STAT3/NF-κB pathway. This intervention resulted in reduced release of pro-inflammatory mediators and decreased apoptosis as evidenced by downregulation of Bax, upregulation of Bcl-2, and reductions in renal injury markers KIM-1 and NGAL.

CONCLUSION

sgp130Fc confers renoprotective effects in a murine model of sepsis by selectively targeting the IL-6 trans-signaling pathway and modulating STAT3/NF-κB signaling to inhibit inflammation and apoptosis. These findings highlight the therapeutic potential of sgp130Fc in SAKI and support further clinical investigation.