Endothelial Dysfunction Promotes Calcific Aortic Valve Disease in Chronic Kidney Disease

• Applicant: Professor Dr. Berend Isermann
• Subject Area: Toxicology, Laboratory Medicine ; Nephrology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 561256525

The prevalence of calcified aortic valve disease (CAVD) is rising with increasing life expectancy. CAVD is more frequent and progresses faster in patients suffering from chronic kidney disease (CKD). Currently, no effective therapies are available for CKD-CAVD. Endothelial dysfunction, senescence, sterile inflammation and osteogenic differentiation are key factors in its multifactorial pathogenesis. The interplay between aortic valve endothelial cells (VEC), valvular interstitial cells (VIC) and immune cells orchestrates the remodeling of the valve leaflets and promotes CKD-CAVD. Inflammation and loss of the vasculo-protective functions creates a vicious cycle, promoting inflammation, vascular dysfunction, and extracellular matrix remodeling, all leading to heart valve degeneration. Our long-term goal is to identify and characterize mechanisms driving CKD-CAVD. We hypothesize that CKD induces endothelial dysfunction and senescence in valve endothelial cells, triggering inflammatory and matrix-remodeling responses. To test this hypothesis, we have three specific aims: Aim 1: Identify possible pathomechanisms and their kinetics in CKD-CAVD; Aim 2: Determine the pathogenic role of endothelial dysfunction for these pathomechanisms in CKD-CAVD; Aim 3: Targeting endothelial dysfunction, sterile inflammation and senescence to improve CKD-CAVD. Our in vivo approach includes the use of two rodent models for kinetic analyses and targeted interventions: 5/6 nephrectomy mice and high adenine – high phosphate feed rats to induce CKD-CAVD. Additionally, we will use an inducible model of isolated endothelial dysfunction to determine its pathogenic role in CKD-CAVD and associated sterile inflammation. Ex vivo analyses will include histology, immunoblotting, immunohistochemistry, snRNA sequencing, snDNA methylation sequencing, pyrosequencing, CyTOF, and Olink. Using these multiparametric data we aim to identify common pathways in the two rodent CKD models, and cross-check these with those identified in the endothelial-dysfunction model. This is expected to identify candidate pathways which will be validated in human tissues and blood samples. In a hypothesis-driven approach we will evaluate possible strategies to target CKD-CAVD. The expected outcomes include identifying initiators and drivers of CKD-CAVD at early stages, mechanisms perpetuating CKD-CAVD, and new biomarkers which can be used for medical diagnoses and patient stratification. The results will have an immediate positive impact by providing a better understanding of the onset and progression of CKD-CAVD and a long-term impact by laying the groundwork for developing diagnostic strategies and therapies to treat CKD-CAVD.

• DFG Programme: Research Grants
• International Connection: Israel
• Partner Organisation: The Israel Science Foundation
• Cooperation Partner: Professor Mony Shuvy