Department of Nutrition and Food Hygiene, College of Public Health, Zhengzhou University, Zhengzhou, 450001, Henan, China.
President's Office, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, Henan, China.
Apoptosis. 2024 Oct;29(9-10):1780-1792. doi: 10.1007/s10495-024-01955-4. Epub 2024 Apr 1.
Diabetic nephropathy (DN) is a serious public health problem worldwide, and ferroptosis is deeply involved in the pathogenesis of DN. Prediabetes is a critical period in the prevention and control of diabetes and its complications, in which kidney injury occurs. This study aimed to explore whether ferroptosis would induce kidney injury in prediabetic mice, and whether vitamin D (VD) supplementation is capable of preventing kidney injury by inhibiting ferroptosis, while discussing the potential mechanisms. High-fat diet (HFD) fed KKAy mice and high glucose (HG) treated HK-2 cells were used as experimental subjects in the current study. Our results revealed that serious injury and ferroptosis take place in the kidney tissue of prediabetic mice; furthermore, VD intervention significantly improved the kidney structure and function in prediabetic mice and inhibited ferroptosis, showing ameliorated iron deposition, enhanced antioxidant capability, reduced reactive oxygen species (ROS) and lipid peroxidation accumulation. Meanwhile, VD up-regulated Klotho, solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) expression, and down-regulated p53, transferrin receptor 1 (TFR1) and Acyl-Coenzyme A synthetase long-chain family member 4 (ACSL4) expression. Moreover, we demonstrated that HG-induced ferroptosis is antagonized by treatment of VD and knockdown of Klotho attenuates the protective effect of VD on ferroptosis in vitro. In conclusion, ferroptosis occurs in the kidney of prediabetic mice and VD owns a protective effect on prediabetic kidney injury, possibly by via the Klotho/p53 pathway, thus inhibiting hyperglycemia-induced ferroptosis.
糖尿病肾病（DN）是全球范围内严重的公共卫生问题，铁死亡在 DN 的发病机制中深度参与。糖尿病前期是糖尿病及其并发症防控的关键时期，在此期间发生肾损伤。本研究旨在探讨铁死亡是否会导致糖尿病前期小鼠的肾脏损伤，以及维生素 D（VD）补充是否能够通过抑制铁死亡来预防肾脏损伤，并讨论其潜在机制。本研究使用高脂肪饮食（HFD）喂养的 KKAy 小鼠和高糖（HG）处理的 HK-2 细胞作为实验对象。我们的研究结果表明，糖尿病前期小鼠的肾脏组织发生严重损伤和铁死亡；此外，VD 干预可显著改善糖尿病前期小鼠的肾脏结构和功能，并抑制铁死亡，表现为铁沉积改善、抗氧化能力增强、活性氧（ROS）和脂质过氧化积聚减少。同时，VD 上调 Klotho、溶质载体家族 7 成员 11（SLC7A11）和谷胱甘肽过氧化物酶 4（GPX4）的表达，下调 p53、转铁蛋白受体 1（TFR1）和长链酰基辅酶 A 合成酶家族成员 4（ACSL4）的表达。此外，我们证实 HG 诱导的铁死亡可被 VD 处理拮抗，Klotho 敲低可削弱 VD 对体外铁死亡的保护作用。综上所述，铁死亡发生在糖尿病前期小鼠的肾脏中，VD 对糖尿病前期肾脏损伤具有保护作用，可能是通过 Klotho/p53 通路抑制高血糖诱导的铁死亡。
