Li Jin-Meng, Song Zi-Hua, Li Yuan, Chen Han-Wen, Li Han, Yuan Lu, Li Jing, Lv Wen-Yue, Liu Lei, Wang Na
Department of Clinical Medicine, Jining Medical University, Jining 272013, Shandong Province, China.
Department of General Medicine, Affiliated Hospital of Jining Medical University, Jining 272029, Shandong Province, China.
World J Diabetes. 2025 Mar 15;16(3):97544. doi: 10.4239/wjd.v16.i3.97544.
The pathophysiology of diabetic kidney disease (DKD) is complex. Interfering with the processes of pyroptosis and fibrosis is an effective strategy for slowing DKD progression. Previous studies have revealed that nuclear receptor subfamily 4 group A member 1 (NR4A1) may serve as a novel pathogenic element in DKD; however, the specific mechanism by which it contributes to pyroptosis and fibrosis in DKD is unknown.
To investigate the role of NR4A1 in renal pyroptosis and fibrosis in DKD and possible molecular mechanisms.
Streptozotocin 60 mg/kg was injected intraperitoneally to establish a rat model of DKD. Typically, 45 mmol/L glucose [high glucose (HG)] was used to activate HK-2 cells to mimic the DKD model . HK-2 cells were transfected with NR4A1 siRNA to silence NR4A1.
NR4A1 was elevated in renal tissues of DKD rats and HG-stimulated HK-2 cells. Concurrently, NOD-like receptor protein 3 (NLRP3) and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathways were triggered, and pyroptosis and expression of fibrosis-linked elements was increased and . These alterations were significantly reversed NR4A1 silencing.
Inhibition of NR4A1 mitigated pyroptosis and fibrosis suppressing NLRP3 activation and the PI3K/AKT pathway in HG-activated HK-2 cells.
糖尿病肾病（DKD）的病理生理学较为复杂。干扰细胞焦亡和纤维化过程是减缓DKD进展的有效策略。既往研究表明，核受体亚家族4A组成员1（NR4A1）可能是DKD中的一种新型致病因素；然而，其在DKD中促成细胞焦亡和纤维化的具体机制尚不清楚。
探讨NR4A1在DKD肾细胞焦亡和纤维化中的作用及可能的分子机制。
腹腔注射链脲佐菌素60mg/kg建立DKD大鼠模型。通常，用45mmol/L葡萄糖[高糖（HG）]激活HK-2细胞以模拟DKD模型。用NR4A1 siRNA转染HK-2细胞以沉默NR4A1。
NR4A1在DKD大鼠肾组织和HG刺激的HK-2细胞中升高。同时，NOD样受体蛋白3（NLRP3）和磷脂酰肌醇3激酶（PI3K）/蛋白激酶B（AKT）通路被激活，细胞焦亡及纤维化相关因子的表达增加。NR4A1沉默后，这些改变显著逆转。
抑制NR4A1可减轻HG激活的HK-2细胞中的细胞焦亡和纤维化，其机制可能是通过抑制NLRP3激活和PI3K/AKT通路实现的。
