Xiaolin Wang,Teng Ma,Xiaojian Wan,Yan Meng,Zhenzhen Zhao,Jinjun Bian,Rui Bao,Xiaoming Deng,Tao Yang
IGFBP7 as an early biomarker has been used to identify patients at risk of developing acute kidney injury (AKI). Nevertheless, its role in AKI remains obscure. The aim of our study is to determine the role and mechanism of IGFBP7 in lipopolysaccharide (LPS)-induced HK-2 cells in vitro and on sepsis-induced AKI by cecal ligation and puncture (CLP) in vivo. Here, we identified that IGFBP7 expression was increased in patients with AKI and HK-2 cells with LPS (1, 2, and 5 μg/mL) induction. HK-2 cells with LPS induction showed cell cycle arrest at G1-G0 phases and cell apoptosis and activated ERK1/2 parallel with the changes in the proteins belonging to the ERK1/2 pathway, including Cyclin D1, P21, Bax, and Bcl-2, which were inhibited by the IGFBP7 knockdown. Moreover, IGFBP7 overexpression significantly induced cell cycle arrest at G1-G0 phases and cell apoptosis of HK-2 cells, which were inhibited by PD98509, an ERK1/2 signaling inhibitor. IGFBP7 knockdown effectively alleviated the severity of the renal injury, evidenced by decreases in the urinary levels of creatinine, blood urea nitrogen, and albumin, cell apoptosis, and activation of ERK1/2 signaling in CLP mice. Taken together, our findings indicate that IGFBP7 regulates sepsis-induced AKI through ERK1/2 signaling.
Jimin Cai,Jiacheng Zhang,Nan Wang,Yan Wang,Di Jia,Xin Ge
Introduction 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. Materials and Methods 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). Results 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. Conclusions In summary, IRF1 deficiency mitigated macrophage pyroptosis and protected against HS-induced kidney injury through IGFBP7/IGF1R.
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