MDM2 accelerated renal senescence via ubiquitination and degradation of HDAC1.

Autor: Xiang HL; Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China., Yuan Q; Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China., Zeng JY; Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China., Xu ZY; Department of Nephrology, Henan Provincial People's Hospital, Zhengzhou University, Zhengzhou, 450000, China., Zhang HZ; Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China., Huang J; Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China., Song AN; Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China., Xiong J; Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China., Zhang C; Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China. drzhangchun@hust.edu.cn.
Jazyk: angličtina
Zdroj: Acta pharmacologica Sinica [Acta Pharmacol Sin] 2024 Nov; Vol. 45 (11), pp. 2328-2338. Date of Electronic Publication: 2024 May 17.
DOI: 10.1038/s41401-024-01294-9
Abstrakt: Senescence, an intricate and inevitable biological process, characterized by the gradual loss of homeostasis and declining organ functions. The pathological features of cellular senescence, including cell cycle arrest, metabolic disruptions, and the emergence of senescence-associated secretory phenotypes (SASP), collectively contribute to the intricate and multifaceted nature of senescence. Beyond its classical interaction with p53, murine double minute gene 2 (MDM2), traditionally known as an E3 ubiquitin ligase involved in protein degradation, plays a pivotal role in cellular processes governing senescence. Histone deacetylase (HDAC), a class of histone deacetylases mainly expressed in the nucleus, has emerged as a critical contributor to renal tissues senescence. In this study we investigated the interplay between MDM2 and HDAC1 in renal senescence. We established a natural aging model in mice over a 2-year period that was verified by SA-β-GAL staining and increased expression of senescence-associated markers such as p21, p16, and TNF-α in the kidneys. Furthermore, we showed that the expression of MDM2 was markedly increased, while HDAC1 expression underwent downregulation during renal senescence. This phenomenon was confirmed in H 2 O 2 -stimulated HK2 cells in vitro. Knockout of renal tubular MDM2 alleviated renal senescence in aged mice and in H 2 O 2 -stimulated HK2 cells. Moreover, we demonstrated that MDM2 promoted renal senescence by orchestrating the ubiquitination and subsequent degradation of HDAC1. These mechanisms synergistically accelerate the aging process in renal tissues, highlighting the intricate interplay between MDM2 and HDAC1, underpinning the age-related organ function decline.
(© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)
Databáze: MEDLINE
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