Kynurenine Promotes Phosphate-Induced Endothelial Calcification via Endothelial-to-Mesenchymal Transition, Osteoblastic Differentiation and AhR Activation

In end-stage renal disease (ESRD), the accumulation of solutes normally excreted by the kidneys contributes to multiple complications, including vascular calcification (VC), a key factor in the heightened cardiovascular risk seen in these patients. Among VC drivers, hyperphosphatemia and the uremic milieu are major contributors. Kynurenine, a tryptophan metabolite classified as a uremic toxin, may further exacerbate this process. This study investigated whether kynurenine amplifies high phosphate (Pi)-induced calcification in human aortic endothelial cells (HAEC). Cells were treated with Pi and kynurenine for up to seven days. Kynurenine increased Pi-induced calcium deposition by 36%, accompanied by enhanced endothelial-to-mesenchymal transition (EndMT) and osteoblastic differentiation. Mechanistically, kynurenine activated the aryl hydrocarbon receptor (AhR) pathway, and pharmacological inhibition of AhR partially attenuated this effect. These findings suggest that kynurenine contributes to VC in ESRD by potentiating phosphate-induced endothelial dysfunction via AhR signaling.