Abstract: TH-PO0841
Tri-Omic Analysis Identifies a Glomerular-Specific Epigenetic Vulnerability in Hydralazine-Induced Vasculitis
Session Information
- Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
- 1900 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
Authors
- Capriles, Guido M., TriHealth Inc, Cincinnati, Ohio, United States
- Abdeltawwab, Mohannad, TriHealth Inc, Cincinnati, Ohio, United States
- Rajput, Amit K., TriHealth Inc, Cincinnati, Ohio, United States
Background
Hydralazine-induced ANCA-associated vasculitis (AAV) presents as severe crescentic glomerulonephritis. Hydralazine systemically inhibits DNA methyltransferases (DNMTs) to facilitate autoimmunity via epigenetic de-repression, but mechanisms restricting necrosis to the renal microvasculature remain unclear. We hypothesized the glomerulus possesses a distinct spatial transcriptomic architecture conferring localized vulnerability to hydralazine, a signal masked in bulk tissue analyses.
Methods
An in-silico pipeline evaluated microvascular vulnerability. The Comparative Toxicogenomics Database (CTD) extracted the gene-disease network linking hydralazine to AAV. The Genotype-Tissue Expression (GTEx) portal compared bulk transcript expression (Transcripts Per Million, TPM) of this network in human renal cortex versus systemic arteries. Single-nucleus RNA/ATAC sequencing (snRNA/ATAC-seq) via the Kidney Interactive Transcriptomics (KIT) database mapped spatial co-localization and chromatin accessibility across renal cell clusters.
Results
CTD analysis revealed 797 hydralazine-interacting genes overlap with the AAV network, including ICAM1, TNF, CCL4, EDN1, and COL4A6. GTEx demonstrated "tubular masking"; kidney cortex showed lower bulk baseline expression of the ICAM1 anchor (TPM=17.13) versus systemic aorta (TPM=22.75). Spatial deconvolution via KIT snRNA-seq revealed ICAM1 is highly expressed in renal endothelial clusters, yet absent from dominant tubular populations. Conversely, executioners (TNF, CCL4, EDN1) exhibited minimal RNA expression but robust open chromatin (ATAC signal), indicating an "epigenetically poised" state. The structural target, COL4A6, co-localized to this specific microvascular niche.
Conclusion
This analysis provides a framework for localized renal toxicity. Data indicate bulk RNA-sequencing misses microvascular vulnerabilities due to tubular signal dilution. At single-cell resolution, restricted localization of the ICAM1 anchor to the endothelium, combined with COL4A6 and epigenetically poised chemokines, suggests a structurally primed microenvironment. Findings support a model where hydralazine-induced DNMT inhibition selectively de-represses silenced inflammatory signals at this microvascular anchor, driving targeted crescentic destruction.