Fetuin-A decrease induced by a low-protein diet enhances vascular calcification in uremic rats with hyperphosphatemia

Although dietary phosphate restriction is important for treating hyperphosphatemia in patients with chronic kidney disease, it remains unclear whether a low-protein diet (LPD), which contains low phosphate, has beneficial effects on malnutrition, inflammation, and vascular calcification. The effects of LPD on inflammation, malnutrition, and vascular calcification were therefore assessed in rats. Rats were fed a normal diet or diets containing 0.3% adenine and low/normal protein and low/high phosphate. After 6 wk, serum and urinary biochemical parameters, systemic inflammation, and vascular calcification were examined. The protective effect of fetuin-A and albumin were assessed in cultured vascular smooth muscle cells. Rats fed the diet containing 0.3% adenine developed severe azotemia. LPD in rats fed high phosphate induced malnutrition (decreases in body weight, food intake, serum albumin and fetuin-A levels, and urinary creatinine excretion) and systemic inflammation (increases in serum tumor necrosis factor-alpha and urinary oxidative stress marker). LPD decreased the serum fetuin-A level and fetuin-A synthesis in the liver and increased serum calcium-phosphate precipitates. A high-phosphate diet increased aortic calcium content, which was enhanced by LPD. Reduced fetal calf serum in the medium of cultured vascular smooth muscle cells enhanced phosphate-induced formation of calcium-phosphate precipitates in the media and calcification of vascular smooth muscle cells, both of which were prevented by fetuin-A administration. Our results suggest that phosphate restriction by restricting dietary protein promotes vascular calcification by lowering the systemic fetuin-A level and increasing serum calcium-phosphate precipitates and induces inflammation and malnutrition in uremic rats fed a high-phosphate diet.