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

作者：Martinez Moreno Julio M; Herencia Carmen; Montes de Oca Addy; Diaz Tocados Juan M; Vergara Noemi; Jose Gomez Luna M; Lopez Arguello Silvia D; Camargo Antonio; Peralbo Santaella Esther; Rodriguez Ortiz Maria E; C****ejo Antonio; Rodriguez Mariano; Munoz Castaneda Juan R^*; Almaden Yolanda

来源：Clinical Science, 2017, 131(13): 1449-1463.

DOI：10.1042/CS20160807

In chronic kidney disease patients, high phosphate (HP) levels are associated with 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 (VitD) was also investigated. The study was performed in an in vitro model of human aortic smoothmuscle cells (HASMCs). Incubation of cells in an HP (3.3 mM) medium caused an increased expression of the pro-inflammatory mediators intercellular adhesion molecule 1 (ICAM-1), interleukins (ILs) IL-1 beta, IL-6, IL-8 and tumour necrosis factor alpha (TNF-alpha) (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 nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) signalling as demonstrated by the increase in the nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells protein 65 (p65-NF-kappa beta) assessed by Western blotting and confocal microscopy. Since all these events were attenuated by an antioxidant pre-incubation with the radical scavenger Mn(III) tetrakis (4-benzoic acid) porphyrin (MnTBAP), it is suggested that the inflammatory response is upstream mediated by the ROS/RNS-induced activation of NF-kappa beta. Addition of paricalcitol (PC) 3.10(-8) M to cells in HP prevented the phosphate induced ROS/RNS increase, the activation of NF-kappa beta and the cytokine up-regulation. A bimodal effect was observed, however, for different calcitriol (CTR) concentrations, 10(-10) and 10(-12) M attenuated but 10(-8) M stimulated this phosphate induced pro-oxidative and pro-inflammatory response. Therefore, these findings provide novel mechanisms whereby HP may directly favour vascular dysfunctions and new insights into the protective effects exerted by VitD derivatives.

• 出版日期2017-7-1