| Idiopathic hypercalciuria (IH) is a common inherited condition that affects 2–5 percent of the U.S. population and is the most common cause of calcium (Ca) oxalate nephrolithiasis (kidney stones). IH is characterized by normocalcemia, normal to elevated serum 1,25-dihydroxyvitamin D (calcitriol) levels, and increased intestinal Ca absorption. Calcitriol, the major regulator of intestinal Ca transport, is elevated in about half of IH patients and therefore can account for the elevated intestinal Ca absorption. In IH patients with normal serum calcitriol levels, the cause of the elevated intestinal Ca absorption is unknown.; Like humans, rats exhibit spontaneous hypercalciuria. Bushinsky selectively inbred spontaneously hypercalciuric Sprague-Dawley rats to produce a colony of hypercalciuric/stone-forming (GHS) animals. Similar to certain humans with IH, GHS rats have normal serum calcitriol levels and increased intestinal Ca absorption. The enhanced Ca flux is thought to be due to excess vitamin D receptor (VDR) content in the intestine.; Studies determined that the increased VDR content in male GHS rat duodenum is not due to differences in mRNA sequence, baseline level, or transcription and turnover rates. To examine the mechanism of increased VDR content in GHS duodenum, protein half-life was estimated. VDR half-life was significantly longer in GHS animals suggesting a mechanism for increased protein levels.; The functional consequence of the increased VDR content and altered vitamin D-dependent gene mRNA expression in male GHS rats was investigated. Basal protein levels of VDR and calbindin 9 kD, but not calbindin 28 kD, were significantly higher in GHS duodenum and kidney. Calcitriol increased vitamin D-dependent protein levels in a tissue-specific manner with differing expression profiles in GHS and control rats being observed.; We demonstrated increased VDR levels in GHS rat peripheral blood monocytes (PBMs) and examined whether IH humans also have elevated PBM VDR levels. A novel protocol was developed for the isolation of PBMs and subsequent measurement of VDR. PBM VDR levels were significantly higher in IH male, but not female subjects. Furthermore, serum Ca correlated with PBM VDR level in IH males. The study suggests that VDR may be involved in the etiology of human IH. |
