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Mitochondrial calcium uniporter promotes kidney aging in mice through inducing mitochondrial calcium-mediated renal tubular cell senescence.
- Source :
-
Acta pharmacologica Sinica [Acta Pharmacol Sin] 2024 Oct; Vol. 45 (10), pp. 2149-2162. Date of Electronic Publication: 2024 May 24. - Publication Year :
- 2024
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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.<br /> (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)
- Subjects :
- Animals
Humans
Mice
Male
Kidney Tubules metabolism
Kidney Tubules drug effects
Kidney Tubules pathology
Cell Line
Kidney metabolism
Kidney pathology
Kidney drug effects
Cellular Senescence drug effects
Mitochondria metabolism
Mitochondria drug effects
Calcium metabolism
Calcium Channels metabolism
Aging
Reactive Oxygen Species metabolism
Mice, Inbred C57BL
Subjects
Details
- Language :
- English
- ISSN :
- 1745-7254
- Volume :
- 45
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Acta pharmacologica Sinica
- Publication Type :
- Academic Journal
- Accession number :
- 38789496
- Full Text :
- https://doi.org/10.1038/s41401-024-01298-5