High phosphorus diet increases preproPTH mRNA independent of calcium and calcitriol in normal rats

Phosphorus retention favors secondary hyperparathyroidism by decreasing calcitriol synthesis and serum calcium levels. However, a direct effect of high extracellular phosphorus on parathyroid (PTH) function, gene expression, and cell proliferation is still controversial. Normal rats were fed standard (St; 0.6% calcium, 0.6% phosphorus) or high phosphate (HP) diet (0.6% calcium, 1.2% phosphorus) for 18 days. To rule out transient decreases in serum calcium or calcitriol levels, sets of animals were sacrificed at different time periods after the last feeding (2, 4, 8, 12 or 24 hr). The HP diet led to hyperphosphatemia and secondary hyperparathyroidism and maximum differences in PTH levels were observed eight hours after feeding (St 29.4 +/- 15 vs. HP 87.9 +/- 56 pg/ml, mean +/- SD; P = 0.01). High levels induced by the HP diet prevented both hypocalcemia and low calcitriol levels at each study point. The HP diet also promoted a significant increase of PTH mRNA levels that peaked about eight hours after feeding (100% increase). This was confirmed at the cellular level by in situ hybridization. Parathyroid glands from animals fed the HP diet showed a 25% increase in volume with respect to the St diet (P = 0.01), and a typical pattern of hyperplasia was found. Parathyroid vitamin D receptor (VDR) mRNA levels were not modified by the HP diet. In conclusion, parathyroid gene expression per cell and parathyroid cell hyperplasia are stimulated by high dietary phosphorus independently of calcium and calcitriol. This effect is not mediated by alterations in the gene expression of the parathyroid calcitriol receptor. Our findings emphasize the importance of the control of hyperphosphatemia in chronic renal failure patients.