Abstract
Stress-induced premature senescence may be involved in the pathogeneses of acute liver injury. Hexavalent chromium [Cr(VI)], a common environmental pollutant related to liver injury, likely leads to premature senescence in L02 hepatocytes. However, the underlying mechanisms regarding hepatocyte premature senility in Cr(VI) exposure remain poorly understood. In this study, we found that chronic exposure of L02 hepatocytes to Cr(VI) led to premature senescence characterized by increased β-galactosidase activity, senescence-associated heterochromatin foci, G1 phase arrest, and decreased cell proliferation. Additionally, Cr(VI)-induced senescent L02 hepatocytes showed upregulated inflammation-related factors, such as IL-6 and fibroblast growth factor 23 (FGF23), which also exhibited reactive oxygen species (ROS) accumulation derived from mitochondria accompanied with increased concentration of intracellular calcium ions (Ca2+) and activity of nuclear factor kappa B (NF-κB). Of note is that ROS inhibition by N-acetyl-Lcysteine pretreatment not only alleviated Cr(VI)-induced premature senescence but also reduced the elevated intracellular Ca2+, activated NF-κB, and secretion of IL-6/FGF23. Intriguingly, the toxic effect of Cr(VI) upon premature senescence of L02 hepatocytes and increased levels of IL-6/FGF23 could be partially reversed by the intracellular Ca2+ chelator BAPTA-AM pretreatment. Furthermore, by utilizing the NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC), we confirmed that NF-κB mediated IL-6/FGF23 to regulate the Cr(VI)-induced L02 hepatocyte premature senescence, whilst the concentration of intracellular Ca2+ was not influenced by PDTC. To the best of our knowledge, our data reports for the first time the role of ROS-Ca2+-NF-κB signaling pathway in Cr(VI)-induced premature senescence. Our results collectively shed light on further exploration of innovative intervention strategies and treatment targeting Cr(VI)-induced chronic liver damage related to premature senescence.
Highlights
Cellular senescence, originally discovered by Hayflick and Moorhead, has been regarded as a permanent state with cell cycle arrest which is implicated in a number of pathological conditions such as age-related diseases [1]
A state of permanent cell cycle arrest is the representative hallmark of senescence; the results in Figure 1(d) showed that the senescent L02 hepatocytes get arrested in G1 phase, while there was no obvious cell apoptosis in the both groups (Supplementary Figure S1)
It is generally believed that intrahepatic cell senescence is closely related to the pathogenesis of liver diseases, such as liver fibrosis and cirrhosis [32]
Summary
Originally discovered by Hayflick and Moorhead, has been regarded as a permanent state with cell cycle arrest which is implicated in a number of pathological conditions such as age-related diseases [1]. Compelling evidence in recent years has shown that accumulation of senescent cells is the main feature of aging amongst various species [2, 3]. It is believed that cell senescence with the ability to survive rather than divide could be induced by a wide variety of factors, including the cell division limit (termed replicative senescence) and various damaging stimuli (termed stress-induced premature senescence) [3, 4]. Stress-induced premature senescence causes abnormal accumulation of senescent-like cells to damage cell function and tissue repair. Studies have provided vital evidence in the close correlation between premature senescence and liver diseases.
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