南方医科大学Li-li Zhou小组发现，线粒体钙单向传输器通过诱导线粒体钙介导的肾小管细胞衰老促进小鼠肾脏衰老。该项研究成果于2024年5月24日在线发表在《中国药理学报》上。

据介绍，肾小管上皮细胞衰老在促进和加速肾脏衰老及与年龄相关的肾脏纤维化方面起着关键作用。衰老细胞不仅会丧失自我修复能力，而且会转化为衰老相关分泌表型（SASP），从而引发炎症和纤维化。最近的研究表明，线粒体功能障碍是肾小管细胞衰老和肾脏老化的关键，而钙过载和钙依赖性激酶活性异常参与了线粒体功能障碍相关的衰老。

研究人员探讨了线粒体钙过载和线粒体钙离子通道（MCU）在肾脏衰老中的作用。通过比较2个月大和24个月大的小鼠肾脏，研究人员发现衰老肾脏的肾小管细胞中存在钙过载，同时MCU的表达也显著升高。在人类近端肾小管细胞系HK-2中，MCU激动剂精胺（10μM）可显著增加线粒体钙的积累，并诱导活性氧（ROS）的产生，从而导致肾小管细胞衰老和与年龄相关的肾脏纤维化。

相反，使用MCU拮抗剂RU360（10μM）或钙螯合剂BAPTA-AM（10μM）可减少D-gal诱导的ROS生成，恢复线粒体平衡，延缓细胞衰老，保护HK-2细胞免受肾脏衰老的影响。在D-gal诱导的加速衰老小鼠模型中，连续8周隔日给予BAPTA（100μg/kg，腹腔注射）可明显缓解肾小管细胞衰老和纤维化。研究人员认为，MCU在促进肾小管细胞衰老和肾脏老化中起着关键作用。靶向抑制MCU为肾脏衰老的治疗策略提供了新的思路。

附：英文原文

Title: Mitochondrial calcium uniporter promotes kidney aging in mice through inducing mitochondrial calcium-mediated renal tubular cell senescence

Author: Xiong, Ya-bing, Huang, Wen-yan, Ling, Xian, Zhou, Shan, Wang, Xiao-xu, Li, Xiao-long, Zhou, Li-li

Issue&Volume: 2024-05-24

Abstract: Renal tubular epithelial cell senescence plays a critical role in promoting and accelerating kidney aging and age-related renal fibrosis. Senescent cells not only lose their self-repair ability, but also can transform into senescence-associated secretory phenotype (SASP) to trigger inflammation and fibrogenesis. Recent studies show that mitochondrial dysfunction is critical for renal tubular cell senescence and kidney aging, and calcium overload and abnormal calcium-dependent kinase activities are involved in mitochondrial dysfunction-associated senescence. In this study we investigated the role of mitochondrial calcium overload and mitochondrial calcium uniporter (MCU) in kidney aging. By comparing the kidney of 2- and 24-month-old mice, we found calcium overload in renal tubular cells of aged kidney, accompanied by significantly elevated expression of MCU. In human proximal renal tubular cell line HK-2, pretreatment with MCU agonist spermine (10μM) significantly increased mitochondrial calcium accumulation, and induced the production of reactive oxygen species (ROS), leading to renal tubular cell senescence and age-related kidney fibrosis. On the contrary, pretreatment with MCU antagonist RU360 (10μM) or calcium chelator BAPTA-AM (10μM) diminished D-gal-induced ROS generation, restored mitochondrial homeostasis, retarded cell senescence, and protected against kidney aging in HK-2 cells. In a D-gal-induced accelerated aging mice model, administration of BAPTA (100μg/kg. i.p.) every other day for 8 weeks significantly alleviated renal tubuarl cell senescence and fibrosis. We conclude that MCU plays a key role in promoting renal tubular cell senescence and kidney aging. Targeting inhibition on MCU provides a new insight into the therapeutic strategy against kidney aging.

DOI: 10.1038/s41401-024-01298-5

Source: https://www.nature.com/articles/s41401-024-01298-5