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

Shaochun Bai, Hongwei Wang, Jikun Shen, Randal Zhou, David A. Bushinsky, Murray J. Favus

Research output: Contribution to journalArticle

22 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)830-840
Number of pages11
JournalJournal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
Volume25
Issue number4
DOIs
StatePublished - Apr 2010
Externally publishedYes

Fingerprint

Calcitriol Receptors
Snails
Down-Regulation
Hypercalciuria
Kidney
Histones
Intestines
E-Box Elements
Gene Expression
Nephrolithiasis
Proteins
Bone Resorption
Serum
Genetic Promoter Regions
Monocytes
Colon
Animal Models
Bone and Bones
Cell Line

Keywords

  • GHS rats
  • Hypercalciuria
  • Intestine
  • Kidney
  • Snail
  • Vitamin D receptor

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Elevated vitamin D receptor levels in genetic hypercalciuric stone-forming rats are associated with downregulation of snail. / Bai, Shaochun; Wang, Hongwei; Shen, Jikun; Zhou, Randal; Bushinsky, David A.; Favus, Murray J.

In: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, Vol. 25, No. 4, 04.2010, p. 830-840.

Research output: Contribution to journalArticle

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