Zhang Qianjin, Hu Yichuan, Hu Jin-E, Zhang Min
Department of Endocrinology, The Affiliated Shuyang Hospital of Xuzhou Medical University, Suqian City, Jiangsu Province, China.
Drug Dev Res. 2022 Nov;83(7):1697-1706. doi: 10.1002/ddr.21988. Epub 2022 Sep 1.
The worldwide high prevalence of diabetic nephropathy is one of the common causes of renal failure in diabetic patients. Hyperglycemia-caused podocyte injury is considered as a major contributor to diabetic kidney disease, accompanied by a chronic inflammatory condition. Pyroptosis, a characterized inflammatory form of programmed cell death, is believed to be involved in the pathogenesis of diabetic nephropathy. Solasonine (SS) is a natural alkaloid and received attention as a potential anticancer agent. However, its protective effect against hyperglycemia-caused podocyte injury remains to be determined. Our study found that SS alleviates cell apoptosis, and reduces pyroptosis and oxidative damage in high glucose (HG)-treated MPC5 podocytes. Pro-inflammatory cytokines, including interleukin (IL)-1β and IL-18, and caspase-1 activity were markedly suppressed by SS in HG-treated MPC5 podocytes. SS also reduced HG-induced oxidative damage in MPC5 podocytes. Nrf2 expression was activated by SS in vitro under a HG condition. In addition, Nrf2 silencing attenuated the protective effect of SS against apoptosis, pro-inflammatory cytokines release, caspase-1 activity, and oxidative damage in MPC5 podocytes under a HG condition. Taken together, our findings revealed for the first time that SS alleviated high glucose-induced podocyte apoptosis, pyroptosis, and oxidative damage via regulating the Nrf2/NLRP3 signaling pathway. Our results indicate that SS has the potential as a therapeutic agent for podocyte injury in diabetic nephropathy.
糖尿病肾病在全球范围内的高患病率是糖尿病患者肾衰竭的常见原因之一。高血糖导致的足细胞损伤被认为是糖尿病肾病的主要促成因素，同时伴有慢性炎症状态。细胞焦亡是一种程序性细胞死亡的特征性炎症形式，被认为参与了糖尿病肾病的发病机制。澳洲茄碱（SS）是一种天然生物碱，作为一种潜在的抗癌药物受到关注。然而，其对高血糖导致的足细胞损伤的保护作用仍有待确定。我们的研究发现，SS可减轻高糖（HG）处理的MPC5足细胞的细胞凋亡，减少细胞焦亡和氧化损伤。在HG处理的MPC5足细胞中，SS显著抑制了包括白细胞介素（IL）-1β和IL-18在内的促炎细胞因子以及半胱天冬酶-1的活性。SS还减少了HG诱导的MPC5足细胞的氧化损伤。在HG条件下，SS在体外激活了Nrf2的表达。此外，Nrf2沉默减弱了SS对HG条件下MPC5足细胞凋亡、促炎细胞因子释放、半胱天冬酶-1活性和氧化损伤的保护作用。综上所述，我们的研究结果首次揭示，SS通过调节Nrf2/NLRP3信号通路减轻了高糖诱导的足细胞凋亡、细胞焦亡和氧化损伤。我们的结果表明，SS有潜力作为治疗糖尿病肾病中足细胞损伤的药物。
