Calciprotein Nanoparticles in the Acute Response to Phosphate Flux During Chronic Kidney Disease and Medial Vascular Calcification
Loading...
Authors
Rowsell, Tyler S.
Date
Type
thesis
Language
eng
Keyword
phosphate , vascular calcification , chronic kidney disease , calciprotein particles , acute homeostasis
Alternative Title
Abstract
Dysregulated phosphate homeostasis is a hallmark of chronic kidney disease (CKD) progression and elevated serum phosphate is an independent risk factor for cardiovascular disease (CVD). The emergence of calciprotein particles (CPP) as a likely mediator of dysregulated mineral homeostasis during CKD and vascular calcification (VC) has provoked interest into their role in the acute response to changes in circulating phosphate. This study aimed to first characterize the distribution of matured CPPs in the setting of active VC in order to elucidate the physiologic and/or pathologic nature of CPPs in the context of arterial mineral accrual. We employed a pharmacologic hypervitaminosis D model of VC in Sprague-Dawley (SD) rats order to generate active calcification throughout the arterial tree. Within this first report of CPP distribution in the setting of medial VC, we demonstrate that CPP-bound phosphate does not preferentially accrue in calcifying vasculature relative to soluble phosphate. Given the protective nature of CPP-sequestered PO4 in the setting of phosphate flux and VC, we investigated the temporal formation and maturation of CPPs within a closed-reaction system in vitro. A marked acute PO4 buffering profile was revealed, characterized by nearly half of the total in vitro PO4 challenge sequestered into CPP within seconds. Additionally, we uncovered a previously unrecognized characteristic of the use of OsteoSense, a fluorescent bisphosphonate, in CPP quantification by determining it specifically detects nascent/immature forms of CPPs in vitro. Further investigations showed that acute CPP-mediated PO4 sequestration was dependent on the prevailing protein milieu as well as state of CPP maturation. Using our adenine model of CKD in SD rats, ex vivo studies on their serum provided indices of CPP maturation and acute PO4 sequestration, only becoming aberrant with the onset of increased dietary phosphorous (P) and coinciding with the development of VC. These data provide early evidence to support the existence of an acute phosphate buffering system that responds to phosphate stress, which becomes overwhelmed with high dietary P in CKD.