A synthetic anticoagulant, octaparin, attenuates renal ischemia-reperfusion injury via dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin/nuclear factor κB signaling.

BACKGROUND

Renal ischemia-reperfusion injury (IRI) contributes to acute kidney injury by inducing oxidative stress, inflammation, and thromboinflammatory responses. Conventional heparins mitigate IRI, but their use is limited by bleeding and thrombocytopenia.

OBJECTIVES

To evaluate octaparin, a structurally defined synthetic sulfated octasaccharide with anticoagulant activity and minimal bleeding risk, as a novel therapeutic for IRI.

METHODS

Murine renal IRI models and hypoxia/reoxygenation-injured renal tubular epithelial cells were treated with octaparin. Renal function, histopathological changes, fibrosis, apoptosis, oxidative stress, inflammation, and coagulation parameters were systematically evaluated. Dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) engagement and nuclear factor (NF)-κB signaling were analyzed by molecular docking, receptor blockade experiments, and immunoblotting.

RESULTS

Octaparin significantly improved renal function in vivo, attenuated tubular necrosis and fibrosis, and suppressed apoptosis. It also markedly reduced oxidative stress, restored antioxidant enzyme activity, downregulated proinflammatory cytokines, and reduced neutrophil infiltration. In terms of coagulation, octaparin inhibited tissue factor expression and fibrin deposition, thereby alleviating thromboinflammatory responses. In vitro, octaparin similarly suppressed excessive reactive oxygen species bursts, restored antioxidant defenses, reduced inflammatory cytokine release, and inhibited apoptosis in hypoxia/reoxygenation-injured renal tubular epithelial cells. Mechanistically, octaparin binds to the DC-SIGN receptor on renal epithelial cells, inhibiting NF-κB phosphorylation and nuclear translocation, thereby disrupting reactive oxygen species-driven inflammatory cascades via a pathway distinct from classical heparin anticoagulation.

CONCLUSION

Octaparin exerts multifaceted renoprotective effects in IRI by modulating DC-SIGN/NF-κB signaling. Its ability to simultaneously suppress thromboinflammation, oxidative stress, and apoptosis-without the risks associated with conventional heparins-represents a transformative therapeutic strategy for acute kidney injury.