Aortic Valve Remodeling in Chronic Kidney Disease: A Mineralocorticoid Receptor-Driven Mechanism Involving NGAL and TLR4 Pathways

INTRODUCTIONAortic stenosis (AS) is the most prevalent valve heart disease. Renal failure increases the risk of AS and many circulating factors released during chronic kidney disease (CKD) participate to AS pathophysiology. We assessed in this study the role of increased aldosterone levels occurring in CKD as well as MR signaling and its interplay with Neutrophil Gelatinase-Associated Lipocalin (NGAL) in aortic valve interstitial cells (VICs) pathophysiology. METHODSWe conducted in vivo studies using a CKD rat model, including both wild-type (WT) and NGAL knockout (KO-NGAL) animals, for subsequent ex vivo analysis of aortic valves. In parallel, primary rat VICs were used in vitro to assess osteogenic, fibrotic, and inflammatory responses to aldosterone, as well as to identify the key signaling pathways involved. qPCR, Western blot, and ELISA were employed to characterize these pathways. RESULTSOur findings demonstrate that MR signaling plays a central role in AS progression during CKD, as well as in VIC differentiation, inflammation, fibrosis, and calcification, mediated via the TLR4-MyD88 innate immunity pathway in aldosterone-induced responses. Furthermore, NGAL was shown to act downstream of MR to activate TLR4, promoting additional remodeling and calcification in aortic valves and VICs. These results were further validated in human samples from CKD patients. CONCLUSIONOverall, this study identifies a novel signaling pathway in AS pathophysiology in the CKD rat model and in vitro systems, highlighting for the first time the interplay between MR, NGAL, and TLR4 in driving the pathological processes underlying AS in CKD. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=169 HEIGHT=200 SRC="FIGDIR/small/675970v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@c91353org.highwire.dtl.DTLVardef@113b9d4org.highwire.dtl.DTLVardef@d4437org.highwire.dtl.DTLVardef@f9a617_HPS_FORMAT_FIGEXP M_FIG https://BioRender.com/j7vufds C_FIG