High phosphate induces a pro-inflammatory response by vascular smooth muscle cells. Modulation by vitamin D derivatives

In chronic kidney disease patients, high phosphate (HP) levels are associated to cardiovascular disease, the major cause of morbidity and mortality. Since serum phosphate has been independently correlated with inflammation, the present study aimed to investigate an independent direct effect of HP as a pro-inflammatory factor in VSMCs. A possible modulatory effect of vitamin D was also investigated. The study was performed in an in vitro model of human aortic smooth muscle cells (HASMCs). Incubation of cells in a HP (3.3 mM) medium caused an increased expression of the pro-inflammatory mediators ICAM-1, IL-1β, IL-6, IL-8 and TNF-α (not corroborated at the protein levels for ICAM-1), as well as an increase in reactive oxygen/nitrogen species (ROS/RNS) production. This was accompanied by the activation of NF-kB signalling as demonstrated by the increase in the nuclear translocation of NF-kB -p65 assessed by western blotting and confocal microscopy. Since all these events were attenuated by an antioxidant pre-incubation with the radical scavenger MnTBAP, it is suggested that the inflammatory response is up-stream mediated by the ROS/RNS-induced activation of NF-kB. Addition of paricalcitol 3·10-8M to cells in HP prevented the phosphate-induced ROS/RNS increase, the activation of NF-kB and the cytokine up-regulation. A bimodal effect was observed, however, for different calcitriol concentrations, since 10-10 and 10-12M attenuated but 10-8M stimulated this phosp...
Source: Clinical Science - Category: Biomedical Science Authors: Tags: PublishAheadOfPrint Source Type: research