Interferon Regulatory Factor1 Deficiency Ameliorates Hemorrhagic Shock-Induced Kidney Injury Via IGFBP7/IGF1R Pathway

Hemorrhagic shock (HS), a life-threatening condition characterized by significant blood loss, often leads to multiple organ dysfunction, particularly renal impairment. Previous studies have demonstrated that interferon regulatory factor 1 (IRF1) deficiency exerts a protective effect against kidney function deterioration. This study aims to investigate the role of IRF1 in HS-induced renal injury and elucidate its underlying mechanisms.

HS model was established in male Sprague-Dawley rats by inducing shock through femoral artery bloodletting to maintain a mean arterial pressure of 40-50 mmHg for 1 h, followed by resuscitation via intravenous fluid infusion. Three days prior to HS induction, rat kidneys were injected with interfering lentivirus LV-shIRF1 (2 × 10ˆ9 TU/mL, 50 μL/d). For in vitro experiments, human monocyte-derived macrophages were generated by differentiating Tohoku Hospital Pediatrics-1 cells with 50 nM phorbol 12-myristate 13-acetate (PMA). Pyroptosis was subsequently induced by treating the differentiated macrophages with 5 μg/mL lipopolysaccharide (LPS) and 5 mM adenosine triphosphate (ATP).

IRF1 was significantly upregulated in HS-induced rat kidneys. Histologic assays showed that IRF1 deficiency demonstrated that IRF1 deficiency alleviated kidney injury, suppressed inflammatory responses, and reduced cellular pyroptosis. Dual-luciferase reporter assays confirmed that IRF1 bound to the promoter region of insulin-like growth factor binding protein 7 (IGFBP7) and enhanced its transcriptional activity. Co-immunoprecipitation (Co-IP) and Western blot analysis further verified that IGFBP7 physically interacted with insulin like growth factor 1 receptor (IGF1R) protein. Notably, IRF1 knockdown downregulated IGFBP7 expression while concurrently increasing IGF1R phosphorylation in both in vivo and in vitro models. Functional rescue experiments revealed that IGFBP7 overexpression counteracted the suppressive effects of IRF1 deficiency on cellular pyroptosis and inflammation.

In summary, IRF1 deficiency mitigated macrophage pyroptosis and protected against HS-induced kidney injury through IGFBP7/IGF1R.