Abstract: SA-PO627
Molecular Pathways Underlying Vascular Disease in Children With ESKD
Session Information
- Pediatric Nephrology - II
November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Pediatric Nephrology
- 1800 Pediatric Nephrology
Authors
- Bartosova, Maria, UniversitatsKlinikum Heidelberg, Heidelberg, Baden-Württemberg, Germany
- Bernardor, Julie, UniversitatsKlinikum Heidelberg, Heidelberg, Baden-Württemberg, Germany
- Zhang, Conghui, UniversitatsKlinikum Heidelberg, Heidelberg, Baden-Württemberg, Germany
- Herzog, Rebecca, Medizinische Universitat Wien, Wien, Wien, Austria
- Marinovic, Iva, UniversitatsKlinikum Heidelberg, Heidelberg, Baden-Württemberg, Germany
- Melk, Anette, Medizinische Hochschule Hannover, Hannover, Niedersachsen, Germany
- Peters, Verena, UniversitatsKlinikum Heidelberg, Heidelberg, Baden-Württemberg, Germany
- Kratochwill, Klaus, Medizinische Universitat Wien, Wien, Wien, Austria
- Schmitt, Claus Peter, UniversitatsKlinikum Heidelberg, Heidelberg, Baden-Württemberg, Germany
Group or Team Name
- International Pediatric Peritoneal Biobank
Background
Patients with ESKD suffer from exceedingly high cardiovascular disease. Children, devoid of life-style and aging related CVD risk factors, provide highly sensitive and specific insights in early pathomechanisms of vascular disease.
Methods
Arteriolar tissues from 95 non-CKD and 110 ESKD-children (median age 9.2 years) underwent digital histomorphometry. Omental arterioles microdissected from surrounding fat tissue underwent multi-omics, and untargeted and vascular calcification (VC) targeted GSEA/IPA. Key mechanisms were validated by quantitative immunostaining ex vivo and in vitro.
Results
Significant arteriolar lumen obliteration was present in children with ESKD, intima and media thickness increased, and endothelial telomeres were shorter, independent of underlying diseases and sex. Arteriolar inflammatory (CD68+) and pro-fibrotic (pSMAD2/3) activity was increased.
GSEA identified top enriched pathways including telomere extension by telomerase and chromatin histone methylation. IPA cross-omics showed suppression of actin cytoskeleton, tight junction signaling, and focal adhesion. VC pathway analysis identified 30/442 pathways related to actin cytoskeleton, Wnt signaling, extracellular matrix (ECM) organization, complement activation, and osteoblast-like phenotype.
In independent age-matched ESKD cohorts, endothelial methylated histone 3 was reduced and complement system activated compared to non-CKD controls. Actin cytoskeleton interacting proteins gamma actin and profilin-1 were reduced, cofilin-1 unchanged. ECM protein fibronectin-1 was reduced.
In vitro, exposure of endothelial cells to inflammatory cytokines and reactive metabolites reduced transendothelial resistance, increased permeability and impaired sealing junction and cytoskeleton integrity. These effects were prevented by co-incubation with anserine, 3-methylhistidine and alanyl-glutamine, but not by carnosine, L-histidine, 1-methylhistidine and methyl- alanine.
Conclusion
ESKD results in major vascular aging already in early childhood. We provide a first comprehensive analysis of underlying molecular mechanisms and derive a novel potential therapeutic intervention, in vitro preserving endothelial cell barrier integrity.
Funding
- Government Support – Non-U.S.