Quinolinic acid induces cell apoptosis in PC12 cells through HIF-1-dependent RTP801 activation

Abstract

Neurological disease comprises a series of disorders featuring brain dysfunction and neuronal cell death. Among the factors contributing to neuronal death, excitotoxicity induced by excitatory amino acids, such as glutamate, plays a critical role. However, the mechanisms about how the excitatory amino acids induce neuronal death remain elucidated. In this study, we investigated the role of HIF-1α (hypoxia inducible factor-1α) and RTP801 in cell apoptosis induced by quinolinic acid (QUIN), a glutamatergic agonist, in PC12 cells. We found that QUIN at 5 μM increased the expression of HIF-1α significantly with a peak at 24 h. After the treatment with QUIN (5-20 μM) for 24 h, the cells exhibited decreased viability and cell apoptosis with a concomitant increased expression of apoptosis related proteins. QUIN treatment also induced the generation of intracellular reactive oxygen species and RTP801 up-regulation in a HIF-1α-dependent manner that were inhibited by 2-methoxyestradiol, a HIF-1α inhibitor. Importantly, HIF-1 or RTP801 invalidation by siRNA rescued the cell apoptosis induced by QUIN or cobalt chloride, a chemical inducer of HIF-1. Taken together, these findings support the concept that neurotoxicity induced by QUIN is associated with HIF-1-dependent RTP801 activation and provide insight into the potential of RTP801 inhibitor in treatment of neurological disorders.

Hypoxia‐induced apoptosis of mouse spermatocytes is mediated by HIF‐1α through a death receptor pathway and a mitochondrial pathway

“…However, HIF-1α protects Leydig cells from apoptosis by targeting Mcl-1 (an anti-apoptotic member of the Bcl-2 family) during testicular torsion (Palladino et al, 2012). It has been reported that HIF-1α has a pro-apoptotic effect on PC12 cells (Huang et al, 2016) and A549 cells (Wang et al, 2008) and an anti-apoptotic effect on melanoma (Sendoel et al, 2010), chondrocytes (Chang, Huo, Wu, & Zhang, 2014), and glioblastoma (Choksi et al, 2011). We found that HIF-1α has a pivotal pro-apoptotic effect on GC-2 cells during hypoxia treatment.…”

“…However, hypoxia as a cellular stress can induce the apoptosis of non-cancer cells. Several recent studies demonstrated that the cell damage induced by hypoxia is closely related to apoptosis in cardiomyocytes, astrocytes, endothelial cells, muscle cells, and pancreatic cells (Li et al, 2016;Ma et al, 2017;Xu et al, 2016).…”

“…The inhibition of PHD results in both the stabilization and the dimerization of HIF-1α (Favier, Britto, Freyssenet, Bigard, & Benoit, 2015). Recently, several lines of evidence have indicated that HIF-1α is involved in the regulation of cellular apoptosis under hypoxic conditions (Janke et al, 2013;Sendoel, Kohler, Fellmann, Lowe, & Hengartner, 2010) and that inhibition of HIF-1α protects cells against apoptosis injury during ischemia and hypoxia treatment (Huang, Yang, Zhang, Wang, & Li, 2016;Sherman et al, 2016). Therefore, considering the effect of hypoxia on spermatocyte apoptosis and HIF-1α as a key mediator of hypoxia contributing to apoptosis, in this study, we investigated whether and how hypoxia induces spermatocyte apoptosis through the HIF-1α pathway in a mouse pachytene spermatocyte-derived GC-2 cell line.…”

Pulsed Electromagnetic Field Exposure Reduces Hypoxia and Inflammation Damage in Neuron‐Like and Microglial Cells

“…Recently, it has been reported that neuronal HIF‐1α and HIF‐2α deficiency improves neuronal survival in the early acute phase after ischemic stroke (Barteczek et al, ). Moreover, excessive HIF‐1α activation has been associated to neuronal apoptosis in different cellular models of brain injury (Cheng et al, ; Long et al, ; Huang et al, ). In the present article, we have found that PEMFs exposure in PC12 and SH‐SY5Y cells partially reduced hypoxia‐induced HIF‐1α activation.…”

High Salt Elicits Brain Inflammation and Cognitive Dysfunction, Accompanied by Alternations in the Gut Microbiota and Decreased SCFA Production

“…The human gastrointestinal tract harbors trillions of microorganisms, which include at least 1000 different species of known bacteria with more than 3 million genes, and these microorganisms are termed the gut microbiota (GM) [9]. The GM and its metabolites can modulate not only gastrointestinal function but also enter the circulation to affect the brain.…”