Lu Mengqiu, Zhan Zishun, Li Dan, Chen Hengbing, Li Aimei, Hu Jing, Huang Zhijun, Yi Bin
Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China; Clinical Research Center for Critical Kidney Disease in Hunan Province, China.
Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China; Clinical Research Center for Critical Kidney Disease in Hunan Province, China; Center for Experimental Medicine, The Third Xiangya Hospital of Central South University, Changsha, China; Department of Cardiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China.
Redox Biol. 2025 Mar;80:103518. doi: 10.1016/j.redox.2025.103518. Epub 2025 Jan 28.
This research explores the consequences of being exposed to PM contribute to renal injury while also evaluating the protective role of Vitamin D-VDR signaling in alleviating mitochondrial calcium imbalance and oxidative stress in renal tubular cells.
Animal models of chronic PM exposure were used to simulate environmental conditions in wild type and VDR-overexpressing mice specific to renal tubules. In parallel, HK-2 cell lines were treated with PM in vitro. Mitochondrial function, calcium concentration, and oxidative stress markers were assessed. VDR activation, achieved through genetic overexpression and paricalcitol, was induced to examine its effect on mitochondrial calcium uniporter (MCU) expression and mitochondrial calcium regulation.
PM exposure caused significant mitochondrial damage in renal tubular cells, including mitochondrial calcium overload, increased oxidative stress, reduced membrane potential, and diminished ATP production. Elevated MCU expressions were a key contributor to these disruptions. VDR activation effectively reversed these effects by downregulating MCU, restoring mitochondrial calcium balance, reducing oxidative stress, and improving renal function.
This study shows that activating Vitamin D-VDR signaling shields the kidneys from PM-induced damage by reestablishing mitochondrial calcium balance and lowering oxidative stress via inhibition of the MCU. These results unveil a new protective role of VDR in defending against environmental pollutants and suggest that targeting the MCU could offer a potential therapeutic strategy for treating chronic kidney disease linked to pollution exposure.
本研究探讨暴露于细颗粒物（PM）导致肾损伤的后果，同时评估维生素D-维生素D受体（VDR）信号通路在减轻肾小管细胞线粒体钙失衡和氧化应激中的保护作用。
使用慢性暴露于PM的动物模型来模拟野生型和肾小管特异性VDR过表达小鼠的环境条件。同时，在体外用PM处理HK-2细胞系。评估线粒体功能、钙浓度和氧化应激标志物。通过基因过表达和帕立骨化醇实现VDR激活，以检查其对线粒体钙单向转运体（MCU）表达和线粒体钙调节的影响。
暴露于PM导致肾小管细胞线粒体严重损伤，包括线粒体钙超载、氧化应激增加、膜电位降低和ATP生成减少。MCU表达升高是这些破坏的关键因素。VDR激活通过下调MCU、恢复线粒体钙平衡、降低氧化应激和改善肾功能有效地逆转了这些影响。
本研究表明，激活维生素D-VDR信号通路可通过重新建立线粒体钙平衡和通过抑制MCU降低氧化应激来保护肾脏免受PM诱导的损伤。这些结果揭示了VDR在抵御环境污染物方面的新保护作用，并表明靶向MCU可能为治疗与污染暴露相关的慢性肾病提供一种潜在的治疗策略。
