Article Impact Level: HIGH Data Quality: STRONG Summary of Journal of Molecular and Cellular Cardiology, 179, 18–29. https://doi.org/10.1016/j.yjmcc.2023.03.011 Dr. Alexandre Candellier et al.
Points
- Calcific aortic stenosis (CAS) is more prevalent, progresses faster, and has worse outcomes in chronic kidney disease (CKD) patients.
- Indoxyl sulfate (IS), a uremic toxin, influences valvular interstitial cells (VICs) mineralization derived from the aortic valve.
- IS concentration dependently promotes the osteogenic transition and calcification of primary human VICs in an osteogenic medium.
- The pro-mineralization effect of IS is mediated through the aryl hydrocarbon receptor (AhR)-dependent activation of the NF-κB pathway, leading to the release of interleukin-6 (IL-6).
- Targeting inflammatory pathways, such as NF-κB and IL-6, may reduce the onset and progression of CKD-related CAS, highlighting potential therapeutic strategies.
Summary
Calcific aortic stenosis (CAS) exhibits increased prevalence, earlier onset, faster progression, and worse outcomes in patients with chronic kidney disease (CKD). Indoxyl sulfate (IS), a uremic toxin, has been identified as a powerful predictor of cardiovascular mortality in CKD patients and a significant contributor to ectopic calcification. However, the role of IS in CAS remains poorly understood. This research aimed to investigate the influence of IS on the mineralization of primary human valvular interstitial cells (VIC) derived from the aortic valve.
Primary hVICs were subjected to varying concentrations of IS within an osteogenic medium (OM). The osteogenic transition of hVICs was monitored by quantifying BMP2 and RUNX2 mRNA expression using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Cell mineralization was evaluated using the o-cresol phthalein complex one method. Inflammation levels were assessed by measuring NF-κB activation through Western blot analysis and quantifying IL-1β, IL-6, and TNF-α secretion using enzyme-linked immunosorbent assays (ELISAs). Silencing of the aryl hydrocarbon receptor (AhR) with small interfering RNA (siRNA) was employed to investigate the involved signaling pathways.
The results demonstrated that IS concentration-dependently enhanced the osteogenic transition and calcification of hVICs in the presence of OM. The pro-mineralization effect of IS was mitigated by silencing AhR, the receptor for IS. Furthermore, IS exposure led to p65 phosphorylation, instrumental in IS-induced mineralization. Silencing of AhR or p65 effectively suppressed IS-induced IL-6 secretion by hVICs. Neutralization of IL-6 with an anti-IL-6 antibody counteracted the pro-calcific effects of IS.
In summary, this study reveals that IS promotes the mineralization of hVICs through AhR-dependent activation of the NF-κB pathway, subsequently triggering the release of IL-6. Targeting inflammatory pathways may hold promise for reducing the onset and progression of CKD-related CAS. Further investigations are warranted to explore the potential therapeutic strategies targeting these pathways in managing CKD-associated CAS.
Link to the article: https://www.jmcc-online.com/article/S0022-2828(23)00056-1/fulltext
References Candellier, A., Issa, N., Grissi, M., Brouette, T., Avondo, C., Gomila, C., Blot, G., Gubler, B., Touati, G., Bennis, Y., Caus, T., Brazier, M., Choukroun, G., Tribouilloy, C., Kamel, S., Boudot, C., Hénaut, L., Eltchaninoff, H., Bellien, J., … Vézier, C. (2023). Indoxyl-sulfate activation of the AhR- NF-κB pathway promotes interleukin-6 secretion and the subsequent osteogenic differentiation of human valvular interstitial cells from the aortic valve. Journal of Molecular and Cellular Cardiology, 179, 18–29. https://doi.org/10.1016/j.yjmcc.2023.03.011
