C/EBPß-TFAM-Mediated NLRP3 Inflammasome Activation Contributes to Arsenic-Induced Rat Kidney Injury.

Compelling evidence has demonstrated that arsenic (As) exposure is associated with kidney injuries. Given that inflammatory responses and immune imbalances are the root causes of several kidney diseases, this study investigated the potential mechanisms underlying NLRP3 inflammasome activation in As-induced kidney injury. A rat model of sub-chronic As exposure was established via oral administration of NaAsO2. The results revealed that urinary ß-2-microglobulin (ß2-MG), N-acetyl-ß-D-glucosidase (NAG) and albumin (ALB) were increased in the As-exposed group, reflecting kidney impairment. Moreover, significant glomerular vacuole-like changes, tubular dilatation and inflammatory cell infiltration were observed. Meanwhile, the expression levels of neutrophil gelatinase-associated lipocalin (NGAL), IL-1ß and IL-18 were enhanced in the kidney tissues of As-treated rats. Further, increased expression of NLRP3, ASC and caspase-1, which are NLRP3 inflammasome-associated proteins, were observed in the kidney tissues of rats in the As-treated groups. The expression levels of the NLRP3 upstream regulators C/EBPß and TFAM were also elevated. These findings suggest that sub-chronic As exposure triggers inflammatory responses in rat kidney tissue and impairs kidney function. The underlying mechanisms may be related to the C/EBPß-TFAM pathway and activation of the NLRP3 inflammasome pathway.

Transformer 2 alpha homolog is a downstream gene of hypoxia-inducible factor 1 subunit alpha and is involved in the progression of pancreatic cancer.

Intratumoral hypoxia is a common feature of pancreatic cancer (PC) and also plays a role in its progression. However, hypoxia-regulated signatures in PC are still not completely understood. This study aimed to identify core hypoxia-associated genes and determine their underlying molecular mechanisms in PC cells. Transformer 2 alpha homolog (TRA2A) was found to be an important hypoxia-associated gene, which was upregulated in PC tissues and in PC cells cultured under hypoxia. High TRA2A expression was associated with advanced stage, poor differentiation, and lymph node metastasis. Under normoxic and hypoxic conditions, knockdown of TRA2A both markedly suppressed PC cell proliferation and motility in vitro and in vivo, as well as activation of the AKT pathway. Hypoxia-inducible factor 1 subunit alpha (HIF1α) upregulated the transcription of TRA2A by directly binding to its promoter. TRA2A showed a co-expression relationship with HIF1α in PC tissues. Overexpression of TRA2A alleviated the pro-inhibitive functions of HIF1α-inhibition on PC cell proliferation and motility under hypoxia. In conclusion, TRA2A is a crucial downstream gene of HIF1α that accelerates the proliferation and motility of PC cells. TRA2A may be a novel and practical molecular target for investigating the hypoxic response of PC cells.Abbreviations: TRA2A, transformer 2A protein; PC, pancreatic cancer; HIF1α, hypoxia-inducible factor 1-alpha; GEO, Gene Expression Omnibus; IHC, immunohistochemical staining.