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Regulation of Renal Calcium Receptor Gene Expression by 1,25-Dihydroxyvitamin D₃ in Genetic Hypercalciuric Stone-Forming Rats

Jim J. Yao^*, Shaochun Bai^*, Alexander J. Karnauskas^*, David A. Bushinsky and Murray J. Favus^*

^* The University of Chicago Pritzker School of Medicine, Chicago, Illinois; and The University of Rochester School of Medicine, Rochester, New York

Address correspondence to: Dr. Murray J. Favus, The University of Chicago, Pritzker School of Medicine, 5841 S. Maryland Avenue, MC 1027, Chicago, IL 60637. Phone: 773-702-6227; Fax: 773-702-4274; mfavus{at}medicine.bsd.uchicago.edu

Received for publication December 15, 2004. Accepted for publication February 14, 2005.

Hypercalciuria in inbred genetic hypercalciuric stone-forming (GHS) rats is due, in part, to a decrease in renal tubule Ca reabsorption. Activation of the renal Ca receptor (CaR) may decrease renal tubule Ca reabsorption and cause hypercalciuria through suppression of Ca-sensitive potassium channel activity. Because the rat renal CaR gene is regulated by extracellular calcium and 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] and GHS rats have increased renal vitamin D receptor content, the current study was undertaken to determine the level of CaR gene expression in GHS rat kidney and whether CaR gene expression is regulated by 1,25(OH)₂D₃. Male GHS and normal control (NC) rats were fed a Ca-sufficient diet (0.6% Ca). Western blotting revealed a four-fold increase in CaR protein in GHS rat renal tissue, and 1,25(OH)₂D₃ administration increased renal CaR in both GHS and NC rats. Northern blot analysis of extracts of renal cortical tissue from GHS and NC rats revealed a major 7-kb transcript of CaR and a more modest 4-kb transcript, both of which were readily detectable. Both Northern blotting and real-time reverse transcription–PCR revealed increased basal CaR mRNA expression levels in GHS rat kidney. 1,25(OH)₂D₃ administration increased renal CaR mRNA levels 2.0- and 3.3-fold in GHS and NC rats, respectively. Despite the greater incremental increase by 1,25(OH)₂D₃ in NC rats, CaR mRNA levels remained higher in GHS rat kidney, and the elevation was more sustained. 1,25(OH)₂D₃ increased CaR mRNA through both elevated CaR gene expression and prolonged tissue half-life. These results demonstrate that GHS rats have high levels of CaR gene expression and CaR protein that may contribute to the hypercalciuria and calcium nephrolithiasis.

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