Magnesium inhibits peritoneal calcification as a late-stage characteristic of encapsulating peritoneal sclerosis.

Peritoneal calcification is a prominent feature of the later stage of encapsulating peritoneal sclerosis (EPS) in patients undergoing long-term peritoneal dialysis (PD). However, the pathogenesis and preventive strategy for peritoneal calcification remain unclear. Peritoneum samples from EPS patients were examined histologically. Peritoneal calcification was induced in mice by feeding with an adenine-containing diet combined with intraperitoneal administration of lipopolysaccharide and a calcifying solution containing high calcium and phosphate. Excised mouse peritoneum, human mesothelial cells (MeT5A), and mouse embryonic fibroblasts (MEFs) were cultured in calcifying medium. Immunohistochemistry confirmed the appearance of osteoblastic differentiation-marker-positive cells in the visceral peritoneum from EPS patients. Intraperitoneal administration of magnesium suppressed peritoneal fibrosis and calcification in mice. Calcifying medium increased the calcification of cultured mouse peritoneum, which was prevented by magnesium. Calcification of the extracellular matrix was accelerated in Met5A cells and MEFs treated with calcification medium. Calcifying medium also upregulated osteoblastic differentiation markers in MeT5A cells and induced apoptosis in MEFs. Conversely, magnesium supplementation mitigated extracellular matrix calcification and phenotypic transdifferentiation and apoptosis caused by calcifying conditions in cultured MeT5A cells and MEFs. Phosphate loading contributes to the progression of EPS through peritoneal calcification and fibrosis, which can be prevented by magnesium supplementation.

Protective Roles of Xenotropic and Polytropic Retrovirus Receptor 1 (XPR1) in Uremic Vascular Calcification.

Cellular phosphate transporters play critical roles in the pathogenesis of vascular calcification (VC) in chronic kidney disease (CKD). However, the mechanistic link between VC and xenotropic and polytropic receptor 1 (XPR1), a newly identified phosphate exporter, remains unknown. We developed a new mouse model with rapidly progressive uremic VC in C57BL/6 mice and examined the roles of XPR1. The combination of surgical heminephrectomy and 8 weeks of feeding a customized warfarin and adenine-based diet induced extensive aortic VC in almost all mice. The XPR1 mRNA level in the aorta of CKD mice was significantly lower than those in control mice as early as week 2, when there was no apparent VC, which progressively declined thereafter. Dietary phosphate restriction increased XPR1 mRNA expression in the aorta but reduced aortic VC in CKD mice. In cultured vascular smooth muscle cells (VSMCs), a calcifying medium supplemented with high phosphate and calcium did not affect XPR1 mRNA expression. The XPR1 mRNA expression in cultured VCMCs was also unaffected by administration of indoxyl sulfate or calcitriol deficiency but was decreased by 1-34 parathyroid hormone or fibroblast growth factor 23 supplementation. Furthermore, XPR1 deletion in the cultured VSMCs exacerbated calcification of the extracellular matrix as well as the osteogenic phenotypic switch under the condition of calcifying medium. Our data suggest that XPR1 plays protective roles in the pathogenesis of VC and its decrease in the aorta may contribute to the progression of VC in CKD.