Fibrillin-1 Orchestrates a Pro-senescent Niche Driving Peritubular Endothelial Senescence via ZEB1/endothelin-1/β-catenin Signaling.

Abstract

Microvascular rarefaction is a predominant pathological hallmark of chronic kidney disease (CKD), functioning simultaneously as a catalyst and consequence of progressive renal compromise. Although endothelial senescence constitutes a cardinal mediator of microvascular attrition in CKD, its upstream regulatory mechanism remains elusive. Here, using integrated single-cell/spatial transcriptomics, decellularized scaffold modeling, diverse murine CKD models, vascular ultrasonography, and tissue-clearing-enabled 3D imaging, we identify fibrillin-1 (FBN1), a core constituent of the fibrogenic niche, as an architect of a pro-senescent microenvironment that directly triggers endothelial senescence. Mechanistically, FBN1 upregulates the transcription factor ZEB1, which binds to the EDN1 promoter to enhance endothelin-1 (ET-1) transcription, thereby activating the ET-1/β-catenin signaling axis to execute cellular senescence. This cascade is abolished by ZEB1 knockdown, ET-1 receptor antagonism, or β-catenin inhibition. Importantly, tubule-specific Fbn1 deletion suppresses endothelial senescence, attenuates capillary rarefaction, and ameliorates renal function across CKD models. Our study unveils the FBN1/ZEB1/ET-1/β-catenin axis as a spatially organized signaling pathway linking to endothelial senescence, demonstrating how matrix-embedded components actively perpetuate pathogenesis by orchestrating stable pathological microenvironments. These findings provide a conceptual framework for CKD-associated vascular deterioration and highlight microenvironmental reprogramming as a therapeutic paradigm.