期刊
JOURNAL OF BONE AND MINERAL RESEARCH
卷 25, 期 4, 页码 830-840出版社
WILEY
DOI: 10.1359/jbmr.091010
关键词
GHS RATS; VITAMIN D RECEPTOR; HYPERCALCIURIA; INTESTINE; KIDNEY; SNAIL
资金
- National Institutes of Health (NIH) [DK 075462]
- University of Chicago
- Elizabeth H Malott University of Chicago
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)(2)D] levels are elevated or normal in IH and are normal in OHS rats In OHS 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)(2)D 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 OHS 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 OHS compared with normal control intestine and was accompanied by hyperacetylation of histone H-3 These results provide evidence that elevated VDR in OHS rats likely occurs because of derepression resulting from reduced Snail binding to the VDR promoter and hyperacetylation of histone H-3 (C) 2010 American Society for Bone and Mineral Research
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