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

• Published in: Journal of bone and mineral research Vol. 25; no. 4; pp. 830 - 840
• Main Authors: Bai, Shaochun, Wang, Hongwei, Shen, Jikun, Zhou, Randal, Bushinsky, David A, Favus, Murray J
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.04.2010; Wiley; Wiley Subscription Services, Inc
• Subjects: Acetylation; Animals; Biological and medical sciences; Cell Line; Colon - metabolism; Down-Regulation; E-Box Elements - genetics; Female; Fundamental and applied biological sciences. Psychology; Gene Expression; GHS rats; Histones - metabolism; Humans; hypercalciuria; Hypercalciuria - genetics; Hypercalciuria - metabolism; Hypercalciuria - urine; Intestinal Mucosa - metabolism; intestine; kidney; Kidney Calculi - genetics; Kidney Calculi - metabolism; Male; Original; Promoter Regions, Genetic; Rats; Rats, Sprague-Dawley; Receptors, Calcitriol - analysis; Receptors, Calcitriol - genetics; Receptors, Calcitriol - metabolism; Skeleton and joints; Snail; Snail Family Transcription Factors; Transcription Factors - analysis; Transcription Factors - genetics; Transcription Factors - metabolism; Vertebrates: osteoarticular system, musculoskeletal system; vitamin D receptor; GHS RATS; Rat; Digestive system; Rodentia; Gut; INTESTINE; Kidney; Osteoarticular system; Vertebrata; Mammalia; Hypercalciuria; Urinary system; Vitamin D; VITAMIN D RECEPTOR; Genetics; Biological receptor; SNAIL
• ISSN: 0884-0431; 1523-4681
• DOI: 10.1359/jbmr.091010

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.