Fibrillin-1 orchestrates pro-senescent niche, driving endothelial senescence in CKD via ZEB1/ET-1/β-catenin pathway

Chronic kidney disease (CKD) is a progressive global health burden characterized by microvascular rarefaction, a critical pathological hallmark that both causes and results from renal compromise. Endothelial senescence is a cardinal mediator of this microvascular attrition, yet its upstream regulatory mechanisms remain largely undefined. Current standard-of-care treatments often fail to halt disease progression effectively, highlighting an urgent need for novel therapeutic targets. This study investigates how extracellular matrix components contribute to this pathology, specifically focusing on fibrillin-1 (FBN1) and its role in orchestrating a pro-senescent microenvironment.

Researchers employed integrated single-cell/spatial transcriptomics, decellularized scaffold modeling, and diverse murine CKD models to investigate the role of fibrillin-1. They utilized vascular ultrasonography and tissue-clearing-enabled 3D imaging to assess microvascular changes. The primary intervention involved tubule-specific Fbn1 gene deletion in these murine models. Mechanistic studies explored the impact of ZEB1 knockdown, endothelin-1 (ET-1) receptor antagonism, and β-catenin inhibition to dissect the identified signaling cascade. The study aimed to identify the upstream regulators of endothelial senescence and their impact on renal function.

Fibrillin-1 (FBN1), a core component of the fibrogenic niche, was identified as an architect of a pro-senescent microenvironment that directly triggers endothelial senescence. Mechanistically, FBN1 was found to upregulate the transcription factor ZEB1. ZEB1 then binds to the EDN1 promoter, enhancing endothelin-1 (ET-1) transcription, which subsequently activates the ET-1/β-catenin signaling axis to execute cellular senescence. This entire cascade was abolished by ZEB1 knockdown, ET-1 receptor antagonism, or β-catenin inhibition, demonstrating the pathway's dependence on these components. Importantly, tubule-specific Fbn1 deletion consistently suppressed endothelial senescence, attenuated capillary rarefaction, and ameliorated renal function across various CKD models. This suggests a direct and significant role for FBN1 in driving CKD progression.

Tubule-specific Fbn1 deletion suppressed endothelial senescence, attenuated capillary rarefaction, and ameliorated renal function across CKD models.