P21(WAF1) and transforming growth factor-alpha mediate dietary phosphate regulation of parathyroid cell growth

Background. The parathyroid (PT) hyperplasia induced by renal failure can b e further enhanced by high dietary phosphate (P) or completely abolished by P restriction. To identify potential mechanisms mediating these opposing e ffects of dietary P on PT growth, this study first focused on p21(WAF1) (p2 1) because high P reduces while low P enhances serum 1,25-dihydroxyvitamin D, whose potent antiproliferative properties result from the induction of p 21. In addition to reducing p21, high P-induced PT growth could result from increased PT expression of the growth promoter transforming growth factor- cc (TGF-a), known to be elevated in hyperplastic and adenomatous human PT g lands. Methods. The time course for dietary P regulation of PT expression of TGF-a and p21 was assessed for seven days after 5/6 nephrectomy in rats and corr elated with the degree of PT hyperplasia and secondary hyperparathyroidism. Results. In P-restricted 5/6 nephrectomized rats, PT-p21 mRNA and protein i ncreased by day 2, independent of changes in serum 1,25-dihydroxyvitamin D, and remained higher than in the high P counterparts for up to seven days. The PT hyperplasia of the high P group could not be attributed to a reducti on of PT-p21 expression from normal control values. Instead, PTTGF-alpha pr otein was higher in uremic rats compared with normal controls and increased further with high dietary P intake. PT levels of proliferating cell nuclea r antigen (PCNA), an index of cell mitoses, correlated inversely with p21 a nd directly with TGF-a. Consistent with these findings, PT gland size and s erum PT hormone levels, similar in both dietary groups at day 2, were highe r in the high P group by day 5. Induction of p21 by low P and of TGF-alpha by high P was specific for the PT glands. Dietary P had no effect either on intestinal growth or p21 or TGF-alpha protein content. Conclusions. These findings suggest that low P induction of p21 could preve nt PT hyperplasia in early uremia, whereas high P enhancement of TGF-a may function as an autocrine signal to stimulate growth further.