Targeted chelation therapy decreases NLRP3 expression by vascular cells and acts as senomorphic in chronic kidney disorder induced vascular calcification.

OBJECTIVE: This study aimed to evaluate whether EDTA-based targeted chelation therapy can act as senomorphic in chronic kidney disease (CKD)-induced vascular calcification. INTRODUCTION: Vascular calcification, a significant complication of CKD, is induced due to osteogenic trans-differentiation and senescence of vascular smooth muscle cells (VSMCs). Senescent VSMCs contribute to inflammation and calcification via the senescence-associated secretory phenotype (SASP). Recent evidence implicates the NLRP3 inflammasome as a key mediator of inflammation and senescence in vascular calcification. We previously demonstrated that EDTA chelation therapy removes calcium deposits from arteries in the CKD model. In this study, we investigated whether EDTA also exerts senomorphic effects by reducing NLRP3 expression and vascular cell senescence in calcified aortic tissue. METHODS: We used an adenine diet-based rodent model of late-stage CKD and an ex vivo aortic ring culture model to evaluate the senotherapeutic potential of EDTA-loaded human serum albumin nanoparticles tagged with anti-elastin antibody-Flexibzumab (EDTA NPs). For validation, we performed a comparative proteomics analysis on the total proteins harvested from the abdominal aortas of the EDTA-treated and untreated animals. RESULTS: Our results show that targeted chelation therapy with EDTA NPs decreases the percentage of SA-β-gal positive senescent cells in the calcified aorta and acts as senomorphic by decreasing NLRP3 inflammasome formation, which is a primary intracellular source of senescence-associated secretory phenotype (SASP). CONCLUSION: For the first time, the current study provides proof of concept on the senotherapeutic potential of a targeted chelation therapy and its capacity to modulate SASP from the senescent cells accumulated in calcified aorta.