Xanthine dehydrogenase and xanthine oxidase activity and gene expression in renal epithelial cells. Cytokine and steroid regulation.

Abstract

Reactive oxygen species have been implicated in the tissue injury and loss of epithelial barrier function associated with a number of clinical disorders in which disregulated inflammation seems to be a dominant event, such as endotoxemia and viral syndromes. In these disorders, xanthine oxidase (XO) contained within the epithelial cell has been proposed as a major source of injurious reactive oxygen species. This study was undertaken in an effort to understand the regulation of xanthine dehydrogenase (XDH)/XO expression at both the activity and gene expression levels in the epithelial cell under conditions associated with the inflammatory response. The results indicate that TNF, IFN-gamma, IL-6, IL-1, and dexamethasone induce XDH/XO activity in bovine renal epithelial cells (MDBK). This pattern of XDH/XO regulation by cytokines and steroids is analogous to the profile of response seen by acute phase reactants. Metabolic labeling and immunoprecipitation revealed the increase in XDH/XO activity requires new protein synthesis. By Northern analysis, all cytokines and dexamethasone increased the level of the 5-kb XDH/XO mRNA. This increase was not detectable in the presence of actinomycin D but was further induced in the presence of cycloheximide, consistent with the major site of XDH/XO up-regulation occurring at the transcriptional level. XDH/XO mRNA was very stable, with no indication that the rates of transcript degradation contributed to differences in mRNA accumulation or ultimate activity levels. In addition to providing information on the regulation of XDH/XO, the data presented furthers the understanding of the epithelial cell's potential to actively respond to immunomodulators associated with injury/inflammation.

Natural mutations of human XDH promote the nitrite (NO2−)-reductase capacity of xanthine oxidoreductase: A novel mechanism to promote redox health?

“…Numerous pathological stimuli including pro-inflammatory cytokines [ [47] , [48] , [49] ], unhealthy diet [ 50 ], cigarette smoke [ 51 ], hypoxia [ 52 , 53 ], ischemia-reperfusion injury and CVD risk factors (such as hypertension [ 54 ]) increase XOR expression and activity. These stimuli also promote the conversion of XOR from the housekeeping reduced isoform, XDH, to the more detrimental oxidized isoform, XO.…”

C1QBP regulates apoptosis of renal cell carcinoma via modulating xanthine dehydrogenase (XDH) mediated ROS generation

“…Our research showed that these cytokines mRNAs were regulated by C1QBP in RCC cells. Inflammatory cytokines TNF-α, IL6, IL-1β, and IFN-γ have been reported to promote the transcription of XDH [18]. Therefore, we speculated that C1QBP might promote XDH transcription by regulating the expression of these inflammatory cytokines (TNF-α, IL6, and IFN-γ), resulting in ROS production and subsequent induction of apoptosis of RCC cells.…”

“…The expression of XDH is affected by many factors, including inflammatory cytokines, hormones, growth factors, stimuli, etc [14]. Inflammatory cytokines TNF-α, IL6, IL-1β, and IFN-γ have been reported to promote the transcription of XDH [18]. To examine whether C1QBP affects transcriptional stimulators of XDH, we measured the TNF-α, IL6, IL-1β, and IFN-γ mRNA.…”

Natural mutations of humanXDHpromote the nitrite (NO2-)-reductase capacity of xanthine oxidoreductase: a novel mechanism to promote redox health?

“…Numerous pathological stimuli including pro-inflammatory cytokines (50–52), unhealthy diet (53), cigarette smoke (13), hypoxia (14,54), ischemia-reperfusion injury and CVD risk factors (such as hypertension (55)) increase XOR expression and activity. These stimuli also promote the conversion of XOR from the housekeeping reduced isoform, XDH, to the more detrimental oxidized isoform, XO.…”