Work

Uremic toxin p‑cresyl sulfate enhances the calcification of aortic valvular interstitial cells via klotho/sirtuin‑1 signaling

Year: 2026

Type: article

Abstract: Calcific aortic valve disease (CAVD), a valvular heart disease with severe complications, is common in patients with chronic kidney disease (CKD).P-cresyl sulfate (PCS) is a protein-binding uremic toxin that induces chronic inflammation.Klotho and sirtuin-1 (SIRT1) represent potential therapeutic agents for mitigating CKD-induced vascular calcifications.We hypothesized that PCS could enhance valvular interstitial cell (VIC) calcification, which could be modulated by klotho/SIRT1 signaling.Alizarin Red S staining, western blotting and immunohistochemical analysis were performed in order to examine calcification and klotho/SIRT1 signaling in isolated porcine VICs following various 7-day treatments.VIC treatments included incubation with PCS (10 and 100 µM), klotho (100 pM), the hypoxia-inducible factor-1α (HIF-1α) inhibitor PX-478 (0.5 µM) and the SIRT1 activator SRT1720 (1 mM).Furthermore, the present study established a PCS-induced rat model of CKD and analyzed the effects of klotho on runt-related transcription factor 2 (RUNX2) expression in rat aortic valves in vivo.Treatment with PCS increased VIC calcification, NF-κB acetylation and the expression of RUNX2 and HIF-1α expression but was shown to reduce klotho expression.Klotho supplementation attenuated the PCS-induced enhancement of VIC calcification and mitigated PCS-mediated increases in NF-κB acetylation and RUNX2 expression.Additionally, the SIRT1 activator SRT1720 attenuated the PCS-mediated enhancement of VIC calcification and was shown to upregulate klotho and downregulate RUNX2 in PCS-treated VICs.Furthermore, the present study demonstrated that klotho supplementation mitigated CKD-mediated RUNX2 upregulation in the aortic valves of PCS-treated CKD model rats.The present study demonstrated that PCS induced VIC calcification by activating HIF-1α signaling and downregulating klotho.Treatment with klotho or SRT1720 was shown to attenuate PCS-mediated activation of the NF-κB/RUNX2 signaling pathway, suggesting that these agents demonstrate notable therapeutic potential for targeting PCS-induced CAVD.

Source: Molecular Medicine Reports

DOI: 10.3892/mmr.2026.13872