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 (10 μM) 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 (10 μM) or calcium chelator BAPTA-AM (10 μM) 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 (100 μg/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.
摘要：
肾小管上皮细胞衰老在促进和加速肾脏衰老以及年龄相关性肾脏纤维化中起着至关重要的作用。衰老细胞不仅失去自我修复能力,但也可以转化为衰老相关分泌表型（SASP），引发炎症和纤维发生。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衰老的关键,钙超载和异常的钙依赖性激酶活性与线粒体功能障碍相关的衰老有关。在这项研究中，我们调查了线粒体钙超载和线粒体钙单转体（MCU）在肾脏衰老中的作用。通过比较2和24月龄小鼠的肾脏，我们在老年肾脏的肾小管细胞中发现钙超载，伴随着MCU表达的显著升高。在人近端肾小管细胞系HK-2中，用MCU激动剂精胺（10μM）预处理显着增加线粒体钙积累，并诱导活性氧（ROS）的产生，导致肾小管细胞衰老和年龄相关性肾纤维化。相反,用MCU拮抗剂RU360（10μM）或钙螯合剂BAPTA-AM（10μM）预处理减少了D-gal诱导的ROS生成，线粒体恢复了稳态,延缓细胞衰老,并保护HK-2细胞免受肾脏衰老。在D-gal诱导的加速衰老小鼠模型中，施用BAPTA(100μg/kg。i.p.)每隔一天持续8周显著缓解肾小管细胞衰老和纤维化。我们得出结论，MCU在促进肾小管细胞衰老和肾脏衰老中起关键作用。针对MCU的靶向抑制为针对肾脏衰老的治疗策略提供了新的见解。
