Abstract
Vascular calcification is a major complication of maintenance hemodialysis patients. Studies have confirmed that calcification mainly occurs in the vascular smooth muscle cells (VSMC) of the vascular media. However, the exact pathogenesis of VSMC calcification is still unknown. This study shows that the crosstalk between calcium and aldosterone via the allograft inflammatory factor 1 (AIF-1) pathway contributes to calcium homeostasis and VSMC calcification, which is a novel mechanism of vascular calcification in uremia. In vivo results showed that the level of aldosterone and inflammatory factors increased in calcified arteries, whereas no significant changes were observed in peripheral blood. However, the expression of inflammatory factors markedly increased in the peripheral blood of uremic rats without aortic calcification and gradually returned to normal levels with aggravation of aortic calcification. In vitro results showed that there was an interaction between calcium ions and aldosterone in macrophages or VSMC. Calcium induced aldosterone synthesis, and in turn, aldosterone also triggered intracellular calcium content upregulation in macrophages or VSMC. Furthermore, activated macrophages induced inflammation, apoptosis, and calcification of VSMC. Activated VSMC also imparted a similar effect on untreated VSMC. Finally, AIF-1 enhanced aldosterone- or calcium-induced VSMC calcification, and NF-κB inhibitors inhibited the effect of AIF-1 on VSMC. These in vivo and in vitro results suggest that the crosstalk between calcium ions and aldosterone plays an important role in VSMC calcification in uremia via the AIF-1/NF-κB pathway. Local calcified VSMC induced the same pathological process in surrounding VSMC, thereby contributing to calcium homeostasis and accelerating vascular calcification.