Increased sensitivity to 1,25(oh)2d3 in bone from genetic hypercalciuric rats. Krieger, Nancy S., Victoria M. Stathopoulos, and David A. Bushinsky. Department of Medicine, University of Rochester School of Medicine, Rochester, NY 14642
APStracts 3:0016C, 1996.
As a model of human hypercalciuria we have selectively inbred genetic hypercalciuric stone forming (GHS) Sprague-Dawley rats whose mean urine calcium excretion is 8 - 9 times greater than that of controls. A large component of this excess urine calcium excretion is secondary to increased intestinal calcium absorption which is not due to an elevation in serum 1,25(OH)2D3, but appears to result from an increased number of intestinal 1,25(OH)2D3 receptors. When GHS rats are fed a low calcium diet the hypercalciuria is only partially decreased and urine calcium excretion exceeds intake, suggesting that an additional mechanism contributing to the hypercalciuria is enhanced bone demineralization. To determine if GHS rat bones are more sensitive to exogenous 1,25(OH)2D3 we cultured calvariae from neonatal (2-3?day old) GHS and control rats with or without 1,25(OH)2D3 or PTH for 48h at 37oC. There was significant stimulation of calcium efflux from GHS calvariae at 1 and 10 nM 1,25(OH)2D3, while control calvariae showed no significant response to 1,25(OH)2D3 at any concentration tested. In contrast, PTH induced similar bone resorption in control and GHS calvariae. Immunoblot analysis demonstrated a four-fold increase in the level of 1,25(OH)2D3 receptors (VDR) in GHS calvariae compared to control calvariae, similar to the increased intestinal receptors described previously. There was no comparable change in VDR RNA levels as measured by slot blot analysis, suggesting the altered regulation of the VDR occurs posttranscriptionally. That both bone and intestine display an increased amount of 1,25(OH)2D3 receptors, suggests that this may be a systemic disorder in the GHS rat and that enhanced bone resorption may be responsible, in part, for the hypercalciuria in the GHS rat. 

Received 16 June 1995; accepted in final form 29 December 1995.
APS Manuscript Number C347-5.
Article publication pending Am. J. Physiol. (Cell Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 22 January 96