Department of Pathophysiology, Guizhou Medical University, Guiyang, China.
Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, China.
FASEB J. 2021 Jan;35(1):e21239. doi: 10.1096/fj.202002089R.
Etoposide-induced 2.4 (EI24) exerts tumor suppressor activity through participating in cell apoptosis, autophagy, and inflammation. However, its role in renal diseases has not been elucidated. This study showed that the EI24 level decreased gradually in the kidneys of mice with unilateral ureteral obstruction (UUO) and in another fibrosis model induced by diabetic kidney disease. The overexpression of EI24 was used to investigate the possible role both in vivo and in vitro. The overexpression 1 day after UUO through tail vein injection alleviated the progression of renal interstitial fibrosis (RIF). EI24 inhibited epithelial-mesenchymal transition, excessive deposition of the extracellular matrix, and activation of fibroblasts. Furthermore, administration of EI24-overexpressing plasmids restrained the phosphorylation of nuclear factor-κB (NF-κB) and c-Jun kinase (JNK) through regulating the proteasome-dependent degradation of TRAF2, and then, inhibited the expression of downstream inflammation-associated cytokines (interleukin-6, tumor necrosis factor-α, and monocyte chemotactic protein-1) and infiltration of macrophages and neutrophils in mouse kidney after UUO. In conclusion, the data indicated that EI24, a novel anti-fibrosis regulator, was important in the progression of RIF.
依托泊苷诱导的 2.4（EI24）通过参与细胞凋亡、自噬和炎症发挥肿瘤抑制活性。然而，其在肾脏疾病中的作用尚未阐明。本研究表明，单侧输尿管梗阻（UUO）小鼠肾脏和糖尿病肾病诱导的另一种纤维化模型中，EI24 水平逐渐降低。通过尾静脉注射在 UUO 后 1 天过表达 EI24 以研究其在体内和体外的可能作用。过表达后，可缓解肾间质纤维化（RIF）的进展。EI24 抑制上皮-间充质转化、细胞外基质过度沉积和成纤维细胞激活。此外，通过调节 TRAF2 的蛋白酶体依赖性降解，EI24 过表达质粒的给药抑制了核因子-κB（NF-κB）和 c-Jun 激酶（JNK）的磷酸化，从而抑制了 UUO 后小鼠肾脏中炎症相关细胞因子（白细胞介素-6、肿瘤坏死因子-α和单核细胞趋化蛋白-1）的表达和巨噬细胞和中性粒细胞的浸润。总之，数据表明，新型抗纤维化调节剂 EI24 在 RIF 的进展中很重要。
