High serum levels of phosphate are associated with uraemia-induced calcific aortic valve disease (CAVD). However, it is not clear whether hyperphosphataemia is required in all phases of the process. Our aim was to determine the effects of phosphate and phosphate depletion at different phases of valve disease. The experimental design consisted of administering a uraemia-inducing diet, with or without phosphate enrichment, to rats for 7 weeks. Forty-two rats were fed with a phosphate- enriched

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... emic regimen that caused renal insufficiency and hyperphosphataemia. Another 42 rats were fed with a phosphate- depleted uraemic regimen, which induces similar severity of renal insufficiency, but without its related mineral disorder. Aortic valves were evaluated at several points during the time of diet administration. In the second part, 54 rats were fed a phosphate- enriched diet for various time periods and then were switched to a phosphate- depleted diet to complete 7 weeks of uraemic diet. Osteoblast like phenotype, inflammation and eventually valve calcification were observed only in rats that were fed with a phosphate- enriched regimen. Significant valve calcification was observed only in rats that were fed a phosphate- enriched diet for at least 4 weeks. Valve calcification was observed only when the switch to a phosphate- depleted regimen occurred after osteoblast markers and activation of Akt and ERK intracellular signaling pathways had already been found in the valve. Phosphate is essential for the initiation of the calcification process. However, when osteoblast markers are already expressed in valve tissue, phosphate depletion will not halt the disease.