摘要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.