Phosphate and vascular calcification: Emerging role of the sodium-dependent phosphate co-transporter PiT-1

Abstract

Elevated serum phosphate is a risk factor for vascular calcification and cardiovascular events in kidney disease as well as in the general population. Elevated phosphate levels drive vascular calcification, in part, by regulating vascular smooth muscle cell (VSMC) gene expression, function, and fate. The type III sodium-dependent phosphate co-transporter, PiT-1, is necessary for phosphate-induced VSMC osteochondrogenic phenotype change and calcification, and has recently been shown to have unexpected functions in cell proliferation and embryonic development.

Figure 1

Proposed mechanisms of phosphate-induced vascular calcification include vascular smooth muscle cell (VSMC) phenotype change, VSMC apoptosis, elastin degradation, and dysregulation of pro- and anti-calcification mediators. TNAP cleaves pyrophosphate to generate two molecules of phosphate, perpetuating elevated phosphate conditions. PiT-1 is necessary to induce VSMC osteochondrogenic differentiation, and may additionally play a role in protein modulation at the endoplasmic reticulum that results in inactivation of anti-calcification mediators such as osteopontin and matrix Gla protein, though evidence for this is needed. Whether PiT-1 is required for phosphate-driven apoptosis and/or elastin degradation is not yet known. ER endoplasmic reticulum; MMPs matrix metalloproteinases; PiT-1 type III sodium-dependent phosphate cotransporter 1; PPi pyrophosphate; TNAP tissue non-specific alkaline phosphatase.