Phosphate feeding induces arterial medial calcification in uremic mice: role of serum phosphorus, fibroblast growth factor-23, and osteopontin.
Arterial medial calcification is a major complication in patients with chronic kidney disease and is a strong predictor of cardiovascular and all-cause mortality. We sought to determine the role of dietary phosphorus and the severity of uremia on vascular calcification in calcification-prone DBA/2 mice. Severe and moderate uremia was induced by renal ablation of varying magnitudes. Extensive arterial-medial calcification developed only when the uremic mice were placed on a high-phosphate diet. Arterial calcification in the severely uremic mice fed a high-phosphate diet was significantly associated with hyperphosphatemia. Moderately uremic mice on this diet were not hyperphosphatemic but had a significant rise in their serum levels of fibroblast growth factor 23 (FGF-23) and osteopontin that significantly correlated with arterial medial calcification. Although there was widespread arterial medial calcification, there was no histological evidence of atherosclerosis. At early stages of calcification, the osteochondrogenic markers Runx2 and osteopontin were upregulated, but the smooth muscle cell marker SM22alpha decreased in medial cells, as did the number of smooth muscle cells in extensively calcified regions. These findings suggest that phosphate loading and the severity of uremia play critical roles in controlling arterial medial calcification in mice. Further, FGF-23 and osteopontin may be markers and/or inducers of this process.
El-Abbadi
Mohga M
MM
Department of Bioengineering, University of Washington, Seattle, Washington, USA.
Pai
Ashwini S
AS
Department of Bioengineering, University of Washington, Seattle, Washington, USA.
Leaf
Elizabeth M
EM
Department of Bioengineering, University of Washington, Seattle, Washington, USA.
Yang
Hsueh-Ying
HY
Department of Bioengineering, University of Washington, Seattle, Washington, USA.
Bartley
Bryan A
BA
Department of Bioengineering, University of Washington, Seattle, Washington, USA.
Quan
Krystle K
KK
Department of Bioengineering, University of Washington, Seattle, Washington, USA.
Ingalls
Carly M
CM
Department of Bioengineering, University of Washington, Seattle, Washington, USA.
Liao
Hung Wei
HW
Department of Bioengineering, University of Washington, Seattle, Washington, USA.
Giachelli
Cecilia M
CM
Department of Bioengineering, University of Washington, Seattle, Washington, USA. Electronic address: ceci@u.washington.edu.