p21WAF1 and TGF-alpha mediate parathyroid growth arrest by vitamin D and high calcium

Kidney Int. 2001 Dec;60(6):2109-17. doi: 10.1046/j.1523-1755.2001.00042.x.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood / metabolism
  • Calcium, Dietary / administration & dosage*
  • Calcium, Dietary / pharmacology
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / metabolism
  • Cyclins / physiology*
  • Dose-Response Relationship, Drug
  • Ergocalciferols / pharmacology
  • Female
  • Hyperplasia / prevention & control
  • Parathyroid Glands / drug effects*
  • Parathyroid Glands / metabolism
  • Parathyroid Glands / pathology*
  • Parathyroid Hormone / blood
  • Phosphorus, Dietary / administration & dosage
  • Phosphorus, Dietary / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Transforming Growth Factor alpha / metabolism
  • Transforming Growth Factor alpha / physiology*
  • Uremia / physiopathology*
  • Vitamin D / pharmacology*

Substances

  • Calcium, Dietary
  • Cdkn1a protein, rat
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Ergocalciferols
  • Parathyroid Hormone
  • Phosphorus, Dietary
  • Transforming Growth Factor alpha
  • Vitamin D
  • paricalcitol