Elevated Phosphate-Induced Cell Signaling through Phosphate Transporter PiT-1 in Vascular Smooth Muscle Cells
Chavkin, Nicholas Walter
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Vascular calcification (VC) is prevalent in chronic kidney disease and elevated serum inorganic phosphate (Pi) is a recognized risk factor. The type III sodium-dependent phosphate transporter, PiT-1, is required for elevated Pi-induced osteochondrogenic differentiation and matrix mineralization in vascular smooth muscle cells (VSMCs). However, the molecular mechanism(s) by which PiT-1 promotes these processes is unclear. The research presented in this thesis addresses the role of PiT-1 in vascular calcification mechanisms. First, the Pi concentration required to induce osteochondrogenic differentiation and matrix mineralization of mouse VSMCs was found to be much greater than that required for maximal Pi uptake, suggesting a signaling function of PiT-1 that was independent of Pi transport. Next, Pi transport-independent functions of PiT-1 were found to promote responses to elevated Pi in VSMCs, including ERK1/2 phosphorylation, osteochondrogenic differentiation, and matrix mineralization. Finally, elevated Pi was found to induce binding between PiT-1 and RapGEF1 in VSMCs, and RapGEF1 was required for elevated Pi-induced ERK1/2 phosphorylation through a Rap1/B-Raf/Mek1/2 pathway that promotes VSMC phenotype change. Together, the data presented here shows that elevated Pi promotes PiT-1 binding to RapGEF1 and ERK1/2 phosphorylation through Rap1/B-Raf/Mek1/2, which induces osteochondrogenic differentiation and matrix mineralization of VSMCs.
- Bioengineering