Ye Zehua, Yang Songyuan, Chen Lijia, Yu Weimin, Xia Yuqi, Li Bojun, Zhou Xiangjun, Cheng Fan
Department of Urology, Renmin hospital of Wuhan university, Wuhan, 430060.
Department of Urology, Renmin hospital of Wuhan university, Wuhan, 430060.
Phytomedicine. 2025 Jan;136:156302. doi: 10.1016/j.phymed.2024.156302. Epub 2024 Nov 28.
The global incidence of calcium oxalate (CaOx) kidney stones is rising, and effective treatments remain limited. Luteolin (Lut), a naturally flavonoid present in several plants, is recognized for its anti-inflammatory, anti-injury, and neuroprotective effects. However, its effects on CaOx kidney stone formation and the associated kidney damage are still unknown.
Our study seeks to explore the therapeutic impact of Lut on kidney injury and renal fibrosis caused by CaOx crystal and to elucidate the underlying mechanisms.
CaOx stone models were established in mice via intraperitoneal injection of glyoxylate (Gly, 100 mg/kg) for 12 days. Lut (50 mg/kg or 100 mg/kg) was administered intraperitoneally 7 days before and with the period of Gly treatment. Kidney function and histopathology changes in renal tissues were assessed. RNA sequencing was used to explore potential mechanisms between the model and Lut treatment groups. Molecular docking simulations evaluated the interaction between Lut and the downstream target Nr4a1. Moreover, Nr4a1 knockout mice and knockdown plasmids were used to validate the mechanism of Lut in the treatment of CaOx crystal-induced kidney injury.
Lut significantly mitigated kidney injury and renal fibrosis induced by CaOx crystal, as evidenced by improved kidney function, histopathology staining and Western blot analysis. Lut treatment also significantly inhibited lipid peroxidation and mitochondrial injury. In vitro experiments further demonstrated that Lut treatment alleviated injury and fibrosis in HK-2 cells. Mechanistically, RNA sequencing and molecular docking simulations indicated that Lut binds to Nr4a1 to regulate ferroptosis, thereby alleviating kidney injury induced by CaOx crystal. Overexpression of Nr4a1 negated Lut's beneficial effects, whereas Nr4a1 knockout exhibited a protective effect against kidney injury.
Lut exerts its protective effects by inhibiting ferroptosis via targeting Nr4a1-Slc7a11-GPX4 pathway, alleviating kidney injury and renal fibrosis caused by CaOx crystal deposition.
草酸钙（CaOx）肾结石的全球发病率正在上升，而有效的治疗方法仍然有限。木犀草素（Lut）是一种存在于多种植物中的天然黄酮类化合物，以其抗炎、抗损伤和神经保护作用而闻名。然而，其对CaOx肾结石形成及相关肾损伤的影响仍不清楚。
本研究旨在探讨Lut对CaOx晶体所致肾损伤和肾纤维化的治疗作用，并阐明其潜在机制。
通过腹腔注射乙醛酸（Gly，100mg/kg）12天建立小鼠CaOx结石模型。在Gly治疗前7天及治疗期间腹腔注射Lut（50mg/kg或100mg/kg）。评估肾功能和肾组织的组织病理学变化。采用RNA测序探索模型组与Lut治疗组之间的潜在机制。分子对接模拟评估Lut与下游靶点Nr4a1之间的相互作用。此外，利用Nr4a1基因敲除小鼠和基因敲低质粒验证Lut治疗CaOx晶体诱导的肾损伤的机制。
Lut显著减轻了CaOx晶体诱导的肾损伤和肾纤维化，改善肾功能、组织病理学染色及蛋白质免疫印迹分析均证实了这一点。Lut治疗还显著抑制了脂质过氧化和线粒体损伤。体外实验进一步表明，Lut治疗可减轻HK-2细胞的损伤和纤维化。机制上，RNA测序和分子对接模拟表明，Lut与Nr4a1结合以调节铁死亡，从而减轻CaOx晶体诱导的肾损伤。Nr4a1的过表达消除了Lut的有益作用，而Nr4a1基因敲除则对肾损伤具有保护作用。
Lut通过靶向Nr4a1-Slc7a11-GPX4途径抑制铁死亡，减轻CaOx晶体沉积所致的肾损伤和肾纤维化，发挥其保护作用。
