Indoxyl sulfate-induced calcification of vascular smooth muscle cells via the PI3K/Akt/NF-κB signaling pathway.

Vascular calcification (VC) is highly prevalent in patients with chronic kidney disease (CKD) and contributes to their high rate of cardiovascular mortality. Indoxyl sulfate (IS) is a representative protein-bound uremic toxin in CKD patients, which has been recognized as a major risk factor for VC. Recent studies have demonstrated that nuclear factor-kappa B (NK-kappa B) is highly activated in the chronic inflammation conditions of CKD patients and participated in the pathogenesis of VC. However, whether NK-kappa B is involved in the progression of IS-induced VC remains without elucidation. Here, we showed that NK-kappa B activity was increased in the IS-induced calcification of human aortic smooth muscle cells (HASMCs). Blocking the NK-kappa B with a selective inhibitor (Bay-11-7082) significantly relieved the osteogenic transdifferentiation of HASMCs, characterized by the downregulation of early osteogenic-specific marker, core-binding factor alpha subunit 1 (Cbf alpha 1), and upregulation of smooth muscle alpha-actin (alpha-SMA), a specific vascular smooth muscle cell marker. Besides, IS stimulated the activation of PI3K/Akt signaling. Furthermore, LY294002, a specific inhibitor of PI3K/Akt pathway, attenuated the activation of NK-kappa B and osteogenic differentiation of HASMCs. Together, these results suggest that PI3K/Akt/NK-kappa B signaling plays an important role in the pathogenesis of osteogenic transdifferentiation induced by IS.