Original Article

You have full text access to this OnlineOpen article

Elevated vitamin D receptor levels in genetic hypercalciuric stone-forming rats are associated with downregulation of Snail

  1. Shaochun Bai1,
  2. Hongwei Wang1,
  3. Jikun Shen1,
  4. Randal Zhou1,
  5. David A Bushinsky2,
  6. Murray J Favus1,*

Article first published online: 14 DEC 2009

DOI: 10.1359/jbmr.091010

Issue

Journal of Bone and Mineral Research

Journal of Bone and Mineral Research

Volume 25, Issue 4, pages 830–840, April 2010

Additional Information

How to Cite

Bai, S., Wang, H., Shen, J., Zhou, R., Bushinsky, D. A. and Favus, M. J. (2010), Elevated vitamin D receptor levels in genetic hypercalciuric stone-forming rats are associated with downregulation of Snail. J Bone Miner Res, 25: 830–840. doi: 10.1359/jbmr.091010

Author Information

  1. 1

    Section of Endocrinology and Metabolism, The University of Chicago Pritzker School of Medicine, Chicago, IL, USA

  2. 2

    Department of Medicine, University of Rochester School of Medicine, Rochester, New York, USA

*Section of Endocrinology and Metabolism, The University of Chicago, 5841 S. Maryland Ave., MC 1027, Chicago, IL 60637, USA.

Publication History

  1. Issue published online: 9 APR 2010
  2. Article first published online: 14 DEC 2009
  3. Accepted manuscript online: 27 JAN 2010 12:00AM EST
  4. Manuscript Accepted: 9 OCT 2009
  5. Manuscript Revised: 21 SEP 2009
  6. Manuscript Received: 6 FEB 2009

SEARCH

SEARCH BY CITATION

ARTICLE TOOLS

View Full Article (HTML) Get PDF (437K)

Keywords:

  • GHS rats;
  • vitamin D receptor;
  • hypercalciuria;
  • intestine;
  • kidney;
  • Snail

Abstract

Patients with idiopathic hypercalciuria (IH) and genetic hypercalciuric stone-forming (GHS) rats, an animal model of IH, are both characterized by normal serum Ca, hypercalciuria, Ca nephrolithiasis, reduced renal Ca reabsorption, and increased bone resorption. Serum 1,25-dihydroxyvitamin D [1,25(OH)2D] levels are elevated or normal in IH and are normal in GHS rats. In GHS rats, vitamin D receptor (VDR) protein levels are elevated in intestinal, kidney, and bone cells, and in IH, peripheral blood monocyte VDR levels are high. The high VDR is thought to amplify the target-tissue actions of normal circulating 1,25(OH)2D levels to increase Ca transport. The aim of this study was to elucidate the molecular mechanisms whereby Snail may contribute to the high VDR levels in GHS rats. In the study, Snail gene expression and protein levels were lower in GHS rat tissues and inversely correlated with VDR gene expression and protein levels in intestine and kidney cells. In human kidney and colon cell lines, ChIP assays revealed endogenous Snail binding close to specific E-box sequences within the human VDR promoter region, whereas only one E-box specifically bound Snail in the rat promoter. Snail binding to rat VDR promoter E-box regions was reduced in GHS compared with normal control intestine and was accompanied by hyperacetylation of histone H3. These results provide evidence that elevated VDR in GHS rats likely occurs because of derepression resulting from reduced Snail binding to the VDR promoter and hyperacetylation of histone H3. © 2010 American Society for Bone and Mineral Research.

View Full Article (HTML) Get PDF (437K)