Qian Xiaojing, Lin Shan, Li Ji, Jia ChengLin, Luo Yun, Fan Rui, Hu Cheng, Chen Ying
Shanghai TCM-Integrated Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China.
Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Evid Based Complement Alternat Med. 2023 Jan 19;2023:9331546. doi: 10.1155/2023/9331546. eCollection 2023.
Diabetic nephropathy (DN) is one of the most severe microvascular complications of diabetes and has become the leading cause of end-stage renal disease formation. The pathogenesis of diabetic nephropathy is very complex and is still not fully understood. Fisetin is a flavonoid polyphenolic compound that is widely found in different fruits, vegetables, and medicinal plants. Many studies have indicated that it has a variety of pharmacological activities. In this study, we investigated the mechanism of action of fisetin in the protection of DN-induced podocyte injury both in vivo and in vitro. Results showed that fisetin could reduce high glucose (HG)-induced podocyte injury and streptozotocin (STZ)-induced diabetic nephropathy in mice. According to the histopathological staining results, fisetin ameliorated DN-induced glomerular injury in a dose-dependent manner. Western blot and immunofluorescence results showed that fisetin effectively promoted the expression of podocyte functional integrity marker proteins and inhibited the expression of podocyte injury marker proteins. In addition, according to the Western blot and RT-qPCR results, fisetin activates the nuclear translocation of Nrf2 to exert antioxidative stress ability and affects the expression of downstream antioxidant enzymes HO-1, GPX4, and other ferroptosis-related markers, thereby protecting against HG-induced podocyte ferroptosis and oxidative stress injury in DN mice. In summary, this study demonstrated that fisetin could enhance the antioxidative stress capacity of DN mice by promoting the activation of the Nrf2/HO-1/GPX4 signaling pathway in renal tissues, and attenuated HG-induced podocytes injury and STZ-induced DN in mice.
糖尿病肾病（DN）是糖尿病最严重的微血管并发症之一，已成为终末期肾病形成的主要原因。糖尿病肾病的发病机制非常复杂，目前仍未完全明确。非瑟酮是一种黄酮类多酚化合物，广泛存在于不同的水果、蔬菜和药用植物中。许多研究表明它具有多种药理活性。在本研究中，我们在体内和体外研究了非瑟酮保护糖尿病肾病诱导的足细胞损伤的作用机制。结果表明，非瑟酮可减轻高糖（HG）诱导的足细胞损伤以及链脲佐菌素（STZ）诱导的小鼠糖尿病肾病。根据组织病理学染色结果，非瑟酮以剂量依赖的方式改善糖尿病肾病诱导的肾小球损伤。蛋白质免疫印迹和免疫荧光结果表明，非瑟酮有效促进足细胞功能完整性标记蛋白的表达，并抑制足细胞损伤标记蛋白的表达。此外，根据蛋白质免疫印迹和RT-qPCR结果，非瑟酮激活Nrf2的核转位以发挥抗氧化应激能力，并影响下游抗氧化酶HO-1、GPX4和其他铁死亡相关标志物的表达，从而预防糖尿病肾病小鼠中HG诱导的足细胞铁死亡和氧化应激损伤。总之，本研究表明非瑟酮可通过促进肾组织中Nrf2/HO-1/GPX4信号通路的激活来增强糖尿病肾病小鼠的抗氧化应激能力，并减轻HG诱导小鼠足细胞损伤以及STZ诱导的糖尿病肾病。
