The long term goals of this proposal are to improve the understanding of the pathogenesis and molecular basis for the increased intestinal Ca transport in genetic idiopathic hypercalciuric (IH) rats and whether these: findings are generalized to human IH. This colony of IH rats is characterized by hypercalciuria, normocalcemia, elevated duodenal Ca active transport, normal serum 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and spontaneous formation of Ca-containing kidney stones. Thus, the IH rats have many of the features of human IH. Preliminary studies demonstrate a two-fold increase in vitamin D receptor (VDR) binding content in intestine, kidney and splenic monocyte from IH rats. In addition, intestinal VDR mRNA is reduced, not increased. These data form the overall hypothesis that increased enterocyte VDR content is a phenotypic marker for genetic IH rats and that the increased VDR number modulates and amplifies the biologic action of 1,25(OH)2D3. If the increased VDR is critical for the increased intestinal Ca absorption and hypercalciuria, then the hypothesis would predict that the increased VDR is due to either prolongation of turnover of a normal or a mutant VDR; greater VDR tissue content increases vitamin D-dependent biologic functions; and, VDR is increased in all tissues that express the VDR gene. The following 3 specific aims are designed to test the overall hypothesis: 1) Explore the mechanisms whereby VDR is increased in IH rats by: vitamin D-dependence, tissue distribution and content, and developmental appearance of the VDR; identify abnormalities in the exons of the VDR gene of IH rats by PCR amplification of intestinal VDR cDNA; determine VDR message stability and VDR turnover. 2) Test the biological function of increased VDR in tissues in which the VDR is increased by: Ca active transport and VDR content in intestinal segments of high and low transport rates; calbindin 9kd gene expression; 1,25(OH)2D3-induced interleukin 1-beta (IL-1) gene suppression in splenic monocytes; osteocalcin production and 24-hydroxylase activity in calvarial bone cells. 3) With Project 3, determine VDR content and biologic function in accessible tissues from patients with IH: develop VDR measures in peripheral blood monocytes and EBV transformed lymphoblasts; and 1,25(OH)2D3-dependent suppression of IL-1 gene expression. The proposed studies should provide more detailed knowledge of the pathogenesis and molecular basis for genetic IH in the rat model and provide potentially new and useful insights into genetic human IH.

Project Start
1997-09-01
Project End
1999-08-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
5
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Chicago
Department
Type
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637
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Bushinsky, D A; Parker, W R; Asplin, J R (2000) Calcium phosphate supersaturation regulates stone formation in genetic hypercalciuric stone-forming rats. Kidney Int 57:550-60
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Lieske, J C; Huang, E; Toback, F G (2000) Regulation of renal epithelial cell affinity for calcium oxalate monohydrate crystals. Am J Physiol Renal Physiol 278:F130-7
Nakagawa, Y; Asplin, J R; Goldfarb, D S et al. (2000) Clinical use of cystine supersaturation measurements. J Urol 164:1481-5
Bushinsky, D A (1999) Genetic hypercalciuric stone-forming rats. Curr Opin Nephrol Hypertens 8:479-88
Nakagawa, Y; Coe, F L (1999) A modified cyanide-nitroprusside method for quantifying urinary cystine concentration that corrects for creatinine interference. Clin Chim Acta 289:57-68

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