Direct implication of the Calcium Sensing Receptor in Vascular Calcifiction and Atherosclerosis in Chronic Kidney Disease

forthcoming

The principal cause of death in chronic kidney disease (CKD) patients is cardiovascular disease (CVD). Current therapies to treat vascular calcification (VC) and atherosclerosis, which mainly target mineralization and hyperlipidaemia, are not fully effective and have considerable limitations; therefore, additional mechanisms must be investigated. In this respect, hyperphosphatemia is associated with CVD and mortality in CKD patients. Recently, it has been demonstrated that phosphate inhibits Calcium Sensing Receptor (CaSR) signalling, which arise the hypothesis of a direct CaSR implication in vascular (patho)-physiology. Moreover, CaSR promotes opposed effects in vascular smooth muscle cells (VSMC) and osteoblast, preventing calcification in VSMC while increasing mineralization in osteoblast. Given the accumulative evidences that CaSR may exert protective vascular effects, the aim of the AtheroCaSR project is to study whether CaSR activation prevents vascular disorders while preserving bone health. To address this aim, the effects of CaSR modulation will be tested in vitro on VSMC calcification and osteoblastt differentiation under CKD conditions. Then, the effects of the specific CaSR deletion in VSMC will be studied on VC and atherosclerosis in mice with renal insufficiency using novel novel Next-Generation Sequencing for analysis of single cell transcriptome and translational efficiency, with focus on vascular lesions and mineral metabolism. In addition, whether calcimimetics prevent VC and atherosclerosis will be investigated in mice with reduced renal function. Finally, if CaSR modulation directly reduces VSMC microcalcification and atheromatous plaque will be analysed in a cohort of CKD patients treated with calcimimetics. The results from this ambitious study will provide new knowledge on the vascular pathology in CKD and may encourage promising clinical trials and the development of new drugs, having a great impact on CVD-associated mortality in CKD.