Targeted chelation therapy decreases NLRP3 expression by vascular cells and acts as senomorphic in Chronic Kidney Disorder induced Vascular Calcification.

Abstract

BackgroundChronically high levels of phosphate (P) in the serum caused by chronic kidney disease (CKD) induce osteogenic changes in the aortic Vascular Smooth Muscle Cells (VSMCs). Premature onset of cellular senescence is observed in these phenotypically transitioned cells, which plays a critical role in pathology of vascular calcification. We have previously shown that EDTA therapy can remove calcium deposits from the arteries in a rat model of CKD and reduces the expression of osteogenic markers in the aorta. In the current study we evaluated if chelation therapy with EDTA has senotherapeutic potential and could also decrease the accumulation of senescent cells in the aorta once it has calcified. MethodsWe used an adenine diet-based rodent model of late-stage CKD and an ex-vivo aortic ring culture model to evaluate the senotheraputic potential of EDTA loaded-human serum albumin nanoparticles tagged with anti-elastin antibody-Flexibzumab (EDTA-NP). For validation we performed a comparative proteomics analysis on the total proteins harvested from the abdominal aortas of the EDTA nanoparticle treated and untreated animals. ResultsOur results show that targeted chelation therapy with EDTA-NP decreases the percentage of SA-beta gal positive senescent cells in the calcified aorta and acts as senomorphic by decreasing NLRP3 inflammasome formation which is a major intracellular source of Senescence associated secretory phenotype (SASP). ConclusionFor the first time, the current study provides a proof of concept on the senotheraputic potential of a targeted chelation therapy and its capacity to modulate SASP from the senescent cells accumulates in calcified aorta. HighlightsO_LIOur findings show that chelation therapy can act as senomorphic, and increases the life span of rodents suffering from heavy vascular calcification. C_LIO_LIChelation therapy decreases senescent cell accumulation, SASP and NLRP3 expression in the aorta. C_LIO_LIChelation therapy is a novel method for reprogramming senescent cells in the aorta to prevent their phenotypic switching to inflammatory senescent cells and ultimately to osteoblasts. C_LIO_LICurrent data have provided a new hypothesis that agents that restore mineral imbalance in the cellular microenvironment (in this case, EDTA) have the potential to act as senomorphics, which can serve as safer therapeutic alternatives over senolytics to treat vascular calcification by decreasing apoptosis. C_LI