Department of Nephrology, Hebei Medical University Third Hospital, Shijiazhuang City, Hebei Province, China.
Ren Fail. 2024 Dec;46(2):2377785. doi: 10.1080/0886022X.2024.2377785. Epub 2024 Jul 31.
Sirt6, reactive oxygen species and ferroptosis may participate in the pathogenesis of Diabetic Nephropathy (DN). Exploring the relationship between Sirt6, oxidative stress, and ferroptosis provides new scientific ideas to DN.
Human podocytes were stimulated with 30 mM glucose and 5.5 mM glucose. The mice of db/db group were randomly divided into two groups:12 weeks and 16 weeks. Collect mouse blood and urine specimens and renal cortices for investigations. HE, Masson, PAS and immunohistochemical staining were used to observe pathological changes. Western blot, RT-qPCR and immunofluorescence staining were used to evaluate expression of relevant molecules. CCK8 method was introduced to observe cell viability. The changes of podocyte mitochondrial membrane potential and mitochondrial morphology in each group were determined by JC-1 staining and Mito-Tracker.
The expression level of Sirt6, Nrf2, SLC7A11, HO1, SOD2 and GPX4 were reduced, while ACSL4 was increased in DN. Blood glucose, BUN, Scr, TG, T-CHO and 24h urine protein were upregulated, while ALB was reduced in diabetic group. The treatment of Ferrostatin-1 significantly improved these changes, which proved ferroptosis was involved in the development of DN. Overexpression of Sirt6 might ameliorate the oxidation irritable reaction and ferroptosis. Sirt6 plasmid transfection increased mitochondrial membrane potential and protected morphology and structure of mitochondria. The application of Sirt6 siRNA could aggravated the damage manifestations.
High glucose stimulation could decrease the antioxidant capacity and increase formation of ROS and lipid peroxidation. Sirt6 might alleviate HG-induced mitochondrial dysfunction, podocyte injury and ferroptosis through regulating Nrf2/GPX4 pathway.
Sirt6、活性氧和铁死亡可能参与糖尿病肾病（DN）的发病机制。探索 Sirt6、氧化应激和铁死亡之间的关系，为 DN 提供新的科学思路。
用 30mmol/L 葡萄糖和 5.5mmol/L 葡萄糖刺激人足细胞，将 db/db 组小鼠随机分为 12 周和 16 周两组。收集小鼠血、尿标本和肾皮质进行研究。采用 HE、Masson、PAS 和免疫组化染色观察病理变化。Western blot、RT-qPCR 和免疫荧光染色评估相关分子的表达。CCK8 法观察细胞活力。通过 JC-1 染色和 Mito-Tracker 检测各组足细胞线粒体膜电位和线粒体形态的变化。
DN 中 Sirt6、Nrf2、SLC7A11、HO1、SOD2 和 GPX4 的表达水平降低，而 ACSL4 升高。糖尿病组血糖、BUN、Scr、TG、T-CHO 和 24h 尿蛋白升高，ALB 降低。Ferrostatin-1 治疗明显改善了这些变化，证明铁死亡参与了 DN 的发生发展。Sirt6 的过表达可能改善氧化应激反应和铁死亡。Sirt6 质粒转染增加了线粒体膜电位，保护了线粒体的形态和结构。Sirt6 siRNA 的应用加剧了损伤表现。
高糖刺激可降低抗氧化能力，增加 ROS 形成和脂质过氧化。Sirt6 可能通过调节 Nrf2/GPX4 通路缓解 HG 诱导的线粒体功能障碍、足细胞损伤和铁死亡。
