title: Phosphorus restriction prevents parathyroid gland growth. High phosphorus directly stimulates PTH secretion in vitro.
abstract: Dietary phosphorus (P) restriction is known to ameliorate secondary hyperparathyroidism in renal failure patients. In early renal failure, this effect may be mediated by an increase in 1,25-(OH)2D3, whereas in advanced renal failure, P restriction can act independent of changes in 1,25-(OH)2D3 and serum ionized calcium (ICa). In this study, we examined the effects of dietary P on serum PTH, PTH mRNA, and parathyroid gland (PTG) hyperplasia in uremic rats. Normal and uremic rats were maintained on a low (0.2%) or high (0.8%) P diet for 2 mo. PTG weight and serum PTH were similar in both groups of normal rats and in uremic rats fed the 0.2% P diet. In contrast, there were significant increases in serum PTH (130 +/- 25 vs. 35 +/- 3.5 pg/ml, P < 0.01), PTG weight (1.80 +/- 0.13 vs. 0.88 +/- 0.06 microg/gram of body weight, P < 0.01), and PTG DNA (1.63 +/- 0.24 vs. 0.94 +/- 0.07 microg DNA/gland, P < 0.01) in the uremic rats fed the 0.8% P diet as compared with uremic rats fed the 0.2% P diet. Serum ICa and 1,25-(OH)2D3 were not altered over this range of dietary P, suggesting a direct effect of P on PTG function. We tested this possibility in organ cultures of rat PTGs. While PTH secretion was acutely (30 min) regulated by medium calcium, the effects of medium P were not evident until 3 h. During a 6-h incubation, PTH accumulation was significantly greater in the 2.8 mM P medium than in the 0.2 mM P medium (1,706 +/- 215 vs. 1,033 +/- 209 pg/microg DNA, P < 0.02); the medium ICa was 1.25 mM in both conditions. Medium P did not alter PTH mRNA in this system, but cycloheximide (10 microg/ml) abolished the effect of P on PTH secretion. Thus, the effect of P is posttranscriptional, affecting PTH at a translational or posttranslational step. Collectively, these in vivo and in vitro results demonstrate a direct action of P on PTG function that is independent of ICa and 1,25-(OH)2D3.
authors.affiliation: Department of Internal Medicine, Renal Division, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: E
authors.initials: E
authors.lastname: Slatopolsky
authors.forename: J
authors.initials: J
authors.lastname: Finch
authors.forename: M
authors.initials: M
authors.lastname: Denda
authors.forename: C
authors.initials: C
authors.lastname: Ritter
authors.forename: M
authors.initials: M
authors.lastname: Zhong
authors.forename: A
authors.initials: A
authors.lastname: Dusso
authors.forename: P N
authors.initials: PN
authors.lastname: MacDonald
authors.forename: A J
authors.initials: AJ
authors.lastname: Brown
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001806:Blood Urea Nitrogen; D002118:Calcium / Q000494:pharmacology; D002417:Cattle; D002478:Cells, Cultured; D003404:Creatinine / Q000097:blood; D005260:Female; D006801:Humans; D006965:Hyperplasia; D009392:Nephrectomy; D009929:Organ Size; D010280:Parathyroid Glands / Q000187:drug effects / Q000254:growth & development / Q000502:physiology*; D010281:Parathyroid Hormone / Q000097:blood / Q000378:metabolism*; D010758:Phosphorus / Q000172:deficiency* / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D012044:Regression Analysis; D014158:Transcription, Genetic / Q000187:drug effects; D014511:Uremia / Q000097:blood / Q000503:physiopathology*
chemical_list: D010281:Parathyroid Hormone; D012333:RNA, Messenger; D010758:Phosphorus; D003404:Creatinine; D002118:Calcium