Tang Lujun, Yuan Liumei, Ren Di, Huang Jiebin, Liu Renjie, Xia Zhiwei, Huang Na, Zhang Shangbo
Department of Traditional Chinese Medicine, Hunan Aerospace Hospital, No. 189, Fenglin 3rd Road, Yuelu District, Changsha City, 410205, Hunan Province, China.
College of Applied Technology, Hunan Open University, Changsha City, Hunan Province, China.
J Mol Histol. 2025 Sep 24;56(5):327. doi: 10.1007/s10735-025-10609-x.
Podocyte injury from oxidative stress and pyroptosis is closely linked with diabetic kidney disease (DKD). Here, Tetrandrine (TET), derived from tetrandrine root, with anti-inflammatory and antioxidant traits, was studied for its role in podocyte oxidative stress and pyroptosis in DKD. A rat model of DKD was established by high-fat diet feeding combined with intraperitoneal injection of streptozotocin (STZ). Renal function was assessed using urinary albumin to creatinine ratio (UACR), serum creatinine (Scr), and blood urea nitrogen (BUN) levels. Renal pathological morphology was evaluated by hematoxylin-eosin (HE) staining and Masson staining. Malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) were detected with commercially available kits. DCFH-DA probe was used to detect intracellular ROS levels. Western blot detected pyroptosis-related proteins (TXNIP, NLRP3, GSDMD-N, pro-caspase-1). Inflammatory factors (IL-1β and IL-18) levels were detected by enzyme-linked immunosorbent assay (ELISA). Immunofluorescence staining observed the expression and localization of GSDMD. Administration of TET alleviated renal damage in rats with DKD. In DKD rats, TET suppressed the TXNIP/NLRP3/GSDMD pathway, leading to a decrease in oxidative stress and pyroptosis within the renal tissue. In vitro, by inhibiting the TXNIP/NLRP3/GSDMD signaling pathway, TET mitigated podocyte oxidative stress and pyroptosis triggered by high glucose. Following TXNIP overexpressing, podocyte oxidative stress and pyroptosis that TET initially suppressed were subsequently reversed. Our results reveal that TET represses podocyte oxidative stress and pyroptosis through TXNIP/NLRP3/GSDMD pathway, which provides new therapeutic targets for DKD treatment.
氧化应激和细胞焦亡引起的足细胞损伤与糖尿病肾病（DKD）密切相关。本文研究了具有抗炎和抗氧化特性的粉防己碱（TET，源自粉防己根）在DKD足细胞氧化应激和细胞焦亡中的作用。通过高脂饮食联合腹腔注射链脲佐菌素（STZ）建立DKD大鼠模型。采用尿白蛋白与肌酐比值（UACR）、血清肌酐（Scr）和血尿素氮（BUN）水平评估肾功能。通过苏木精-伊红（HE）染色和Masson染色评估肾脏病理形态。使用市售试剂盒检测丙二醛（MDA）、超氧化物歧化酶（SOD）和谷胱甘肽过氧化物酶（GSH-Px）。用DCFH-DA探针检测细胞内活性氧水平。蛋白质免疫印迹法检测细胞焦亡相关蛋白（TXNIP、NLRP3、GSDMD-N、前半胱天冬酶-1）。通过酶联免疫吸附测定（ELISA）检测炎症因子（IL-1β和IL-18）水平。免疫荧光染色观察GSDMD的表达和定位。给予TET可减轻DKD大鼠的肾脏损伤。在DKD大鼠中，TET抑制TXNIP/NLRP3/GSDMD途径，导致肾组织内氧化应激和细胞焦亡减少。在体外，通过抑制TXNIP/NLRP3/GSDMD信号通路，TET减轻了高糖诱导的足细胞氧化应激和细胞焦亡。TXNIP过表达后，TET最初抑制的足细胞氧化应激和细胞焦亡随后被逆转。我们的研究结果表明，TET通过TXNIP/NLRP3/GSDMD途径抑制足细胞氧化应激和细胞焦亡，为DKD治疗提供了新的治疗靶点。
