Abstract：
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 H2O2-stimulated HK2 cells in vitro. Knockout of renal tubular MDM2 alleviated renal senescence in aged mice and in H2O2-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.
摘要：
衰老,一个复杂而不可避免的生物过程，以体内平衡逐渐丧失和器官功能下降为特征。细胞衰老的病理特征，包括细胞周期停滞,代谢中断，和衰老相关分泌表型（SASP）的出现，共同促进衰老的复杂和多方面的性质。除了与p53的经典相互作用，鼠双分钟基因2（MDM2），传统上被称为参与蛋白质降解的E3泛素连接酶，在调节衰老的细胞过程中起着关键作用。组蛋白脱乙酰酶(HDAC),一类主要在细胞核中表达的组蛋白脱乙酰酶，已经成为肾组织衰老的关键因素。在这项研究中，我们调查了MDM2和HDAC1在肾脏衰老中的相互作用。我们在小鼠中建立了2年的自然衰老模型，该模型通过SA-β-GAL染色和肾脏中衰老相关标志物如p21，p16和TNF-α的表达增加来验证。此外，我们发现MDM2的表达明显增加，而HDAC1表达在肾脏衰老过程中下调。这种现象在体外H2O2刺激的HK2细胞中得到证实。肾小管MDM2的敲除减轻了老年小鼠和H2O2刺激的HK2细胞的肾脏衰老。此外，我们证明MDM2通过协调HDAC1的泛素化和随后的降解促进肾脏衰老。这些机制协同加速了肾组织的衰老过程，突出了MDM2和HDAC1之间复杂的相互作用，支撑了与年龄相关的器官功能下降。
