p21WAF1 and TGF-alpha mediate parathyroid growth arrest by vitamin D and high calcium.
BACKGROUND
High dietary phosphorus (P) worsens uremia-induced parathyroid (PT) hyperplasia through increases in the growth promoter transforming growth factor-alpha (TGF-alpha). In contrast, P restriction prevents PT hyperplasia by inducing the cell cycle inhibitor p21. Since 1,25(OH)2D3-antiproliferative action in various cell types involve increases in p21, we studied whether induction of p21 by 1,25(OH)2D3 or the vitamin D analog, 19-Nor-1,25(OH)2D2, could counteract the PT hyperplasia induced by high dietary P in early uremia.


METHODS
Normal (N) and uremic (U; 5/6 nephrectomized) female Sprague-Dawley rats were fed high P (HP), low P (LP) or high Ca (HCa) diets and administered intraperitoneally (IP) either vehicle or vitamin D metabolites for seven days, as follows: N-HP; U-HP + vehicle; U-HP + 1,25(OH)2D3 (4 ng/day); U-HP + 19-Nor-1,25(OH)2D2 (30 ng/day); U-LP; U-HCa. Serum PTH and PT gland weight assessed secondary hyperparathyroidism. Immunohistochemical quantitation of two markers of mitotic activity, Ki67 and PCNA measured PT hyperplasia. Immunohistochemical expression of PT p21 and TGF-alpha addressed potential mechanisms regulating PT cell growth.


RESULTS
1,25(OH)2D3 and 19-Nor-1,25(OH)2D2 were effective in suppressing both PTH secretion and PT hyperplasia induced by uremia and high dietary P independent of increases in ionized Ca. Both vitamin D compounds enhanced PT p21 expression and prevented high P-induced increases in PT TGF-alpha content. Induction of PT p21 and reduction of TGF-alpha content also occurred when uremia-induced PT hyperplasia was suppressed by high dietary Ca.


CONCLUSIONS
In early uremia, vitamin D suppression of high P-induced PT hyperplasia and high dietary Ca arrest of PT growth involve induction of PT p21 and prevention of increases in TGF-alpha.
Cozzolino
M
M
Renal Division, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Lu
Y
Y
Finch
J
J
Slatopolsky
E
E
Dusso
A S
AS
D000818:Animals; D001769:Blood / Q000378:metabolism; D002136:Calcium, Dietary / Q000008:administration & dosage* / Q000494:pharmacology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004872:Ergocalciferols / Q000494:pharmacology; D005260:Female; D006965:Hyperplasia / Q000517:prevention & control; D010280:Parathyroid Glands / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D010281:Parathyroid Hormone / Q000097:blood; D016226:Phosphorus, Dietary / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016211:Transforming Growth Factor alpha / Q000378:metabolism / Q000502:physiology*; D014511:Uremia / Q000503:physiopathology*; D014807:Vitamin D / Q000494:pharmacology*
D002136:Calcium, Dietary; C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004872:Ergocalciferols; D010281:Parathyroid Hormone; D016226:Phosphorus, Dietary; D016211:Transforming Growth Factor alpha; D014807:Vitamin D; C084656:paricalcitol