Chemerin Activation of Toll-Like Receptor 4 Drives Mineralocorticoid Receptor-Mediated Aortic Valve Remodeling in Chronic Kidney Disease.

Abstract

BACKGROUND: Aortic stenosis is the most common valvular heart disease, and its progression is accelerated in chronic kidney disease (CKD), where multiple circulating abnormalities worsen its pathophysiology. This study examined the impact of CKD-related aldosterone excess, focusing on mineralocorticoid receptor signaling and its crosstalk with the innate immune pathway mediated by Toll-like receptor 4 (TLR4) in aortic valve (AV) interstitial cells and AV tissue. METHODS: For the study, we conducted in vivo studies using a CKD rat model challenged with high phosphate, followed by ex vivo analysis of AVs. In parallel, primary rat and human valve interstitial cells were used in vitro to evaluate inflammatory, fibrotic, and osteogenic responses to aldosterone and to identify the key signaling pathways involved. Human AVs from patients with aortic stenosis were also analyzed. Quantitative polymerase chain reaction, western blot, and ELISA were used to characterize these pathways. RESULTS: Mineralocorticoid receptor activation emerged as a central driver of aortic stenosis progression in CKD, promoting valve interstitial cell differentiation, inflammation, fibrosis, and calcification through activation of the TLR4-myeloid differentiation primary response 88 innate immunity pathway in response to aldosterone. Moreover, chemerin was identified as a downstream effector of the mineralocorticoid receptor that activates TLR4, further enhancing remodeling and calcification in AVs and valve interstitial cells. These results were corroborated in human stenotic AV samples from patients with CKD. CONCLUSIONS: Collectively, the study defines a novel mineralocorticoid receptor-TLR4-chemerin axis that mediates aldosterone-driven inflammatory and calcific processes in CKD, in both a rat model and in vitro systems.